ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno,...

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ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico . Poiche’ le cellule tumorali continuano a crescere e a dividersi queste hanno una caratteristica morfologica differente rispetto alle normali cellule. Questa crescita abnorme delle cellule tumorali produce compressione anatomica delle cellule adiacenti e la rapida crescita eccede la capacita vascolare diapportare sangue e nutrimenti portanto a necrosi tissutale. Il tutto porta a cachessia. Nelle cellule cancerose il danno al DNA non e’ riparato e questo DNA danneggiato puo’ essere ereditato. Il DNA e’ danneggiato in seguito ad esposizione ambientale. Raggi ultravioletti, farmaci, asbesto e fumo di sigarette sono cause ambientali ben riconosciute. Anche virus tra I quali

Transcript of ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno,...

Page 1: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

ANTITUMORALI

Il cancro egrave una crescita incontrollata di cellule spesso con comportamento

maligno invasivo e metastatico Poichersquo le cellule tumorali continuano a

crescere e a dividersi queste hanno una caratteristica morfologica differente

rispetto alle normali cellule Questa crescita abnorme delle cellule tumorali

produce compressione anatomica delle cellule adiacenti e la rapida crescita

eccede la capacita vascolare diapportare sangue e nutrimenti portanto a necrosi

tissutale Il tutto porta a cachessia Nelle cellule cancerose il danno al DNA non

ersquo riparato e questo DNA danneggiato puorsquo essere ereditato Il DNA ersquo

danneggiato in seguito ad esposizione ambientale Raggi ultravioletti farmaci

asbesto e fumo di sigarette sono cause ambientali ben riconosciute Anche

virus tra I quali lrsquoHTLV-1 possono essere responsabili di leucemie

Pathogenesis of Neoplasia

Cancer development can begin with a brief exposure (hours or days) to a chemical into an activated form and the chemical need not be present ever again

However DNA is altered via mutagens including chemical carcinogens viruses and radiation This mutations is inherted by at least one cell division (intiation)

This mutation mainly lead to activation of proto-oncogene into oncogenes (leading to uncontrolled cell proliferation) andor inactivation of tumor suppressor genes (leading to resistance to apoptosis)

Upon exposure to other epigenetic factors (hormones co- carcinogens immunosuppressanthellipwhich themselves are non carcinogenic) tumor growth is promoted (promotion)

Gli effetti degli antitumorali sono perciograve anche su cellule non tumorali ed impediscono perciograve la crescita dei peli (capelli) e dellrsquoepitelio intestinale

I tumori ad alto frazione di crescita come la leucemia mieloide acuta linfomi di Hodgkinrsquos sono i piugrave sensibili ai chemioterapici

Un problema dei chemioterapici egrave nei confronti dei tumori solidi in quanto non riescono a raggiungere il centro del tumore Soluzioni a questo problema sono la radioterapia o la chirurgia

Una terapia combinata tra chemioterapia e radioterapia egrave una soluzione al problema

La terapia adiuvante detta anche chemioterapia pre e post -chirurgica ha lo scopo di ridurre la massa tumorale prima dellrsquointervento rendendo cosigrave la terapia locale (chirurgia e radioterapia) meno distruttiva e piugrave efficacePer chemioterapia palliativa si intende quella cura che ha lo scopo di ridurre la massa tumorale aumentando lrsquoaspettativa di vita

CLASSI DI FARMACI ANTITUMORALI

1) Agenti alchilanti

2) Antimetaboliti

3) Antimitotici

4) Alcaloidi di origine vegetale

5) Antibiotici antitumorali

6) Inibitori Topoisomerasi

7) Anticorpi monoclonali

8) Inibitori dei fattori di crescita

AGENTI ALCHILANTI

A) Alchil sulfonati (busulfano)

B) Nitrosouree (Carmustina Lomustina)

C) Mostarde azotate ( Ciclofosfamide Mecloretamina uramustina

Melphalan clorambucile ifosfamide)

D) Composti del Platino (Cis-platino Carboplatino Oxaliplatino)

E) Idrazine (Procarbazina)

F) Tiazine (Dacarbazina)

G) Aziridine (Tiotepa)

Nitrosuree

1) Carmustina2) Streptozocina

Imidazotetrazine

Temozolimide

Lomustina

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 2: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Pathogenesis of Neoplasia

Cancer development can begin with a brief exposure (hours or days) to a chemical into an activated form and the chemical need not be present ever again

However DNA is altered via mutagens including chemical carcinogens viruses and radiation This mutations is inherted by at least one cell division (intiation)

This mutation mainly lead to activation of proto-oncogene into oncogenes (leading to uncontrolled cell proliferation) andor inactivation of tumor suppressor genes (leading to resistance to apoptosis)

Upon exposure to other epigenetic factors (hormones co- carcinogens immunosuppressanthellipwhich themselves are non carcinogenic) tumor growth is promoted (promotion)

Gli effetti degli antitumorali sono perciograve anche su cellule non tumorali ed impediscono perciograve la crescita dei peli (capelli) e dellrsquoepitelio intestinale

I tumori ad alto frazione di crescita come la leucemia mieloide acuta linfomi di Hodgkinrsquos sono i piugrave sensibili ai chemioterapici

Un problema dei chemioterapici egrave nei confronti dei tumori solidi in quanto non riescono a raggiungere il centro del tumore Soluzioni a questo problema sono la radioterapia o la chirurgia

Una terapia combinata tra chemioterapia e radioterapia egrave una soluzione al problema

La terapia adiuvante detta anche chemioterapia pre e post -chirurgica ha lo scopo di ridurre la massa tumorale prima dellrsquointervento rendendo cosigrave la terapia locale (chirurgia e radioterapia) meno distruttiva e piugrave efficacePer chemioterapia palliativa si intende quella cura che ha lo scopo di ridurre la massa tumorale aumentando lrsquoaspettativa di vita

CLASSI DI FARMACI ANTITUMORALI

1) Agenti alchilanti

2) Antimetaboliti

3) Antimitotici

4) Alcaloidi di origine vegetale

5) Antibiotici antitumorali

6) Inibitori Topoisomerasi

7) Anticorpi monoclonali

8) Inibitori dei fattori di crescita

AGENTI ALCHILANTI

A) Alchil sulfonati (busulfano)

B) Nitrosouree (Carmustina Lomustina)

C) Mostarde azotate ( Ciclofosfamide Mecloretamina uramustina

Melphalan clorambucile ifosfamide)

D) Composti del Platino (Cis-platino Carboplatino Oxaliplatino)

E) Idrazine (Procarbazina)

F) Tiazine (Dacarbazina)

G) Aziridine (Tiotepa)

Nitrosuree

1) Carmustina2) Streptozocina

Imidazotetrazine

Temozolimide

Lomustina

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 3: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Gli effetti degli antitumorali sono perciograve anche su cellule non tumorali ed impediscono perciograve la crescita dei peli (capelli) e dellrsquoepitelio intestinale

I tumori ad alto frazione di crescita come la leucemia mieloide acuta linfomi di Hodgkinrsquos sono i piugrave sensibili ai chemioterapici

Un problema dei chemioterapici egrave nei confronti dei tumori solidi in quanto non riescono a raggiungere il centro del tumore Soluzioni a questo problema sono la radioterapia o la chirurgia

Una terapia combinata tra chemioterapia e radioterapia egrave una soluzione al problema

La terapia adiuvante detta anche chemioterapia pre e post -chirurgica ha lo scopo di ridurre la massa tumorale prima dellrsquointervento rendendo cosigrave la terapia locale (chirurgia e radioterapia) meno distruttiva e piugrave efficacePer chemioterapia palliativa si intende quella cura che ha lo scopo di ridurre la massa tumorale aumentando lrsquoaspettativa di vita

CLASSI DI FARMACI ANTITUMORALI

1) Agenti alchilanti

2) Antimetaboliti

3) Antimitotici

4) Alcaloidi di origine vegetale

5) Antibiotici antitumorali

6) Inibitori Topoisomerasi

7) Anticorpi monoclonali

8) Inibitori dei fattori di crescita

AGENTI ALCHILANTI

A) Alchil sulfonati (busulfano)

B) Nitrosouree (Carmustina Lomustina)

C) Mostarde azotate ( Ciclofosfamide Mecloretamina uramustina

Melphalan clorambucile ifosfamide)

D) Composti del Platino (Cis-platino Carboplatino Oxaliplatino)

E) Idrazine (Procarbazina)

F) Tiazine (Dacarbazina)

G) Aziridine (Tiotepa)

Nitrosuree

1) Carmustina2) Streptozocina

Imidazotetrazine

Temozolimide

Lomustina

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 4: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

CLASSI DI FARMACI ANTITUMORALI

1) Agenti alchilanti

2) Antimetaboliti

3) Antimitotici

4) Alcaloidi di origine vegetale

5) Antibiotici antitumorali

6) Inibitori Topoisomerasi

7) Anticorpi monoclonali

8) Inibitori dei fattori di crescita

AGENTI ALCHILANTI

A) Alchil sulfonati (busulfano)

B) Nitrosouree (Carmustina Lomustina)

C) Mostarde azotate ( Ciclofosfamide Mecloretamina uramustina

Melphalan clorambucile ifosfamide)

D) Composti del Platino (Cis-platino Carboplatino Oxaliplatino)

E) Idrazine (Procarbazina)

F) Tiazine (Dacarbazina)

G) Aziridine (Tiotepa)

Nitrosuree

1) Carmustina2) Streptozocina

Imidazotetrazine

Temozolimide

Lomustina

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 5: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

AGENTI ALCHILANTI

A) Alchil sulfonati (busulfano)

B) Nitrosouree (Carmustina Lomustina)

C) Mostarde azotate ( Ciclofosfamide Mecloretamina uramustina

Melphalan clorambucile ifosfamide)

D) Composti del Platino (Cis-platino Carboplatino Oxaliplatino)

E) Idrazine (Procarbazina)

F) Tiazine (Dacarbazina)

G) Aziridine (Tiotepa)

Nitrosuree

1) Carmustina2) Streptozocina

Imidazotetrazine

Temozolimide

Lomustina

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 6: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Nitrosuree

1) Carmustina2) Streptozocina

Imidazotetrazine

Temozolimide

Lomustina

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 7: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Mostarde azotate

Cyclophosphamide

Mecloretamina

Melphalan Clorambucile

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 8: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Composti antitumorali del platino

1) Cisplatino

2) Carboplatino

3) Oxaliplatino

4) Tetranitrato triplatino

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 9: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Idrazine

Procarbazina

Tiazine

Dacarbazina Tiotepa

Aziridine

La dacarbazina egrave un agente alchilante usata nel melanoma maligno nel linfoma di Hodgkin nei sarcomi e nei carcinomi del pancreas

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 10: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Meccanismo di azione degli agenti alchilanti

Gli agenti alchilanti si legano con molte molecole intracellulari tra cui gli acidi

nucleici impedendone la lettura e quindi la trascrizione La citotossicitagrave egrave

primariamente dovuta al legame crociato tra filamenti di DNA ed RNA cosigrave

come allrsquoinibizione della sintesi proteica

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 11: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Resistance to chemotherapy may develop by several mechanisms

Decrease in the amount of drug uptake by cancer cellsEsempio Methotrexate Increase in the amount of drug removed by cancer

cells (Transporters=P-glycoprotein)Esempio Vinblastine doxorubicin bleomycin etapsoidhellip Decrease or alteration in target molecule sensitivity ndash

this is caused by mutation in the molecule targeted by the drug

Esempio MethotrexateMercaptopurinedoxorubicin Increase in DNA repair ability of the cell via an

increased expression of DNA repairing enzymesEsempio Alkylating agent

Problems associated with chemotherapyResistance to chemotherapy

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 12: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Il busulfano egrave il solo agente usato nei regimi di mielosoppressione nei trapianti di cellule staminali ematopoietiche per la quale il monitoraggio terapeutico del farmaco egrave largamente usato Lrsquouso di busulfano per via orale porta ad una grande variabilitagrave intrapaziente e interpaziente in termini farmacocinetici specialmente nei bambini e lrsquoaggiustamento delle dosi egrave necessario per una ridotta tossicitagrave e migliore riuscita terapeutica Lrsquouso di busulfano per via endovenosa sta prendendo piede in quando porta a dei profili farmacocinetici piugrave controllabili La meningite neoplasica rappresenta il 5 dei tumori Ersquo una malattia che colpisce lrsquointero neuroasse e i farmaci devono passare nel fluido cefalorachidiano Oggigiorno la terapia con farmaci direttamente immessi nel liquido cefalorachidiano egrave ristretta a tre farmaci Il metotressato la citarabina ed il tiotepa

Il cis-platino egrave un antitumorale usato per trattare vari tipi di cancro tipo sarcoma carcinosarcomi (piccolo cellule del polmone cancro ovarico) linfomi Ersquo il primo di una classe che va in crescendo di nuovi composti quali il carboplatino lrsquooxaliplatino Questi composti formano dei complessi allrsquointerno della cellula tumorale i quali legano il DNA attraverso legami intracatena e tra catene di DNA A questo segue lrsquoapoptosi cellulare

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 13: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Although the entity we refer today as chronic myeloid leukemia (CML) was probably first described in the early nineteenth century there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 19601 Subsequent important landmarks were the recognition that the Ph chromosome results from a t(922) translocation the demonstration that the leukemia probably originates from a single hematopoietic ldquostem cellrdquo the identification of the breakpoint cluster region (BCR) on chromosome no 22 and subsequently of the BCR-ABL fusion gene and more recently thedevelopment of a murine model simulating the human disease23 Treatment in the 19th century was unsatisfactory although arsenicals induced some degree of symptomatic control In the early 20th century radiotherapy was helpful but it was replaced in the 1950s by busulfan which remained popular for some years despite the emerging suspicion that this alkylating agent might in fact predispose to progression to advanced-phase disease In due course hydroxycarbamide replaced busulfan but interferon-alfa the first agent to induce any degree of Ph-chromosome negativity in the bone marrow was introduced in the early 1980s and became the treatment of choice for patients not eligible for allogeneic stem cell transplantation Between 1980 and 2000 allografting despite the risks of morbidity and mortality was the recommended initial treatment for younger patients with HLA-matched donors Therapy has now been ldquorevolutionizedrdquo by the introduction of imatinib (imatinib mesylate IM) the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998

(Blood 20071102828-2837)

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 14: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Lrsquoosteosarcoma egrave un cancro a carico dellrsquoosso e generalmente colpisce le ossa grandi delle braccia e delle gambe Ersquo presente frequentemente in giovani e sopratutto nei maschi La prognosi dellrsquo osteosarcoma degli arti trattata con solo amputazione puograve essere migliorata drammaticamente includendo la chemioterapia La chemioterapia neoadiuvante egrave comunemente usata per eradicare le micrometastasi e per preparare gli arti alla chirurgia di salvataggioOggi giorno una chirurgia conservativa egrave possibile nella maggior parte dei pazienti incluso i bambini ed egrave anche libera da recidive nei casi di sopravvivenza nel 50-80 Alte dosi di metotressato doxorubicina cis-platino ed ifosfamide sono considerate i

farmaci piugrave attivi contro lrsquoosteosarcoma Bull Cancer 2006 Nov 193(11)1115-20

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 15: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

HODGKIN

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 16: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Definizione del linfoma di Hodgkin Un cancro del sistema immunitario nel quale si evidenzia la presenza di un tipo particolare di cellule dette Reed-Sternberg cell I due tipi principali di linfoma di Hodgkin sono il classico e il nodulare che rappresenta il principale I sintomi includono dolore e ingrossamento dei linfonodi della milza o altri tessuti immunitari Altri sintomi includono febbre perdita di peso fatica e sudorazione notturna

Definizione di linfoma non-Hodgkin Rappresenta una versione di cancro al sistema immunitario (linfociti) Il linfoma non-Hodgkin egrave presente a qualsiasi etagrave e spesso egrave caratterizzato da ingrossamento dei linfonodi febbre e perdita di peso Ci sono diversi tipi di linfoma non-Hodgkin i quali possono essere suddivisi in aggressive (a crescita veloce) e indolenti ( a crescita lenta e possono essere classificati in linfomi delle cellule B o delle cellule T Tra i linfomi delle cellule B ricordiamo il linfoma di Burkitt linfomi diffusi delle cellule B linfomi follicolari linfomi immunoblastici a cellule grandi linfomi di precursori delle cellule B e linfomi di cellule mantello Linfomi non-Hodgkin delle cellule T includono micosi funginee linfomi anaplastici a cellule grandi e linfomi di precursori delle cellule T Linfomi correlati a disordini linfoproliferativi presenti a seguito di trapianti di midollo osseo o di cellule staminali generalmente sono linfomi non-hodgkin di cellule B

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 17: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Reed-Sternberg cell

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 18: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

ANTIMETABOLITI

1) Analoghi dellrsquoacido folico

2) Analoghi delle purine

3) Analoghi delle pirimidine

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 19: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Analoghi dellrsquoacido folico

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 20: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Analoghi dellrsquoacido folico

METOTREXATOIl metotrexato egrave un analogo dellrsquoacido folico e inibisce la diidrofolico reduttasi prevenendo la formazione dellrsquoacido

tetraidrofolico Questo acido egrave essenziale per la formazione delle purine e pirimidine componenti del DNA ed RNA Il

tetraidofolato egrave coinvolto anche nella sintesi di aminoacidi quali serina e metionina

La sua tossicitagrave egrave a carico di cellule ad alta velocitagrave di duplicazione quali quelle del midollo della pelle e dei capelli

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 21: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Leuk Lymphoma 2011 Oct52(10)1882-90 Epub 2011 Jun 12High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphomaGerard LM Imrie KR Mangel J Buckstein R Doherty M Mackenzie R Cheung MCOdette Cancer Centre Sunnybrook Health Sciences Centre Toronto Ontario CanadaAbstract

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL) However combined therapy is associated with increased neurotoxicity In an effort to limit this toxicity we treated a series of non-immunocompromised patients with HDMVP a HD-MTX based regimen with deferral of WBRT until progression Twenty-three patients were treated with the HDMVP regimen consisting of MTX vincristine and procarbazine The mean age at diagnosis was 609 years (range 45-79 years) The overall response rate was 65 (14 complete responses and one partial response)

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 22: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Prog Urol 2011 Jun21(6)369-82

The role of chemotherapy in the management of bladder cancerDeacutepartement doncologie meacutedicale France ismailinabilyahoofrAbstract

Bladder cancer represents for man the second genitourinary cancer after prostate cancer Urothelial carcinoma is the most predominant histological type In up to 70 of the cases the diagnosis of bladder cancer is performed at early stages (Ta-T1) In this situation the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG Amiticyne) In advanced disease treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate vinblastine doxorubicin and cisplatin) or gemcitabine-cisplatin In invasive stages (T2-T3-T4) the radical cystoprostatectomy combined with urinary diversion for man and the pelvectomy for woman are the gold standard

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 23: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

wwwthelancetcom Vol 376 September 25 2010

Metotrexato nellrsquoartrite reumatoide

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 24: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Analoghi delle Purine

Appartengono a questa categoria

1) Azatioprina egrave la principale di questa classe Ersquo largamente utilizzata come immunosoppressivo nei trapianti drsquoorgano prevenendo la moltiplicazione linfocitaria nella fase di induzione del sistema immunitario Interferisce sia attraverso lrsquoinibizione della risposta immunitaria mediata dai linfociti che da quella umurale Ersquo metabolizzata in 6-mercaptopurinea che agisce come analogo delle purine ed inibitore della sintesi del DNA Ersquo usata in caso di autoimmunitagrave 2) Mercaptopurina 3) Tioguanina egrave usata nelle leucemie acute4) Fludarabina inibisce la DNA polimerasi la DNA primasi e ligasi I ed egrave fase specifica

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 25: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Oncotarget 2010 Nov1(7)472-82Refractory chronic lymphocytic leukemia--new therapeutic strategiesSchnaiter A Stilgenbauer SUniversity of Ulm Ulm GermanyAbstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy

Nevertheless refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis Important risk factors are 17p deletion andor mutation of TP53 For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved Meanwhile we have to face also refractoriness to alemtuzumab Importantly the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor Further B-cell antigens are targeted by lumiliximab (CD23) TRU-016 (CD37) and blinatumomab (CD19)

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 26: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Analoghi delle Pirimidine

Appartengono a questa categoria

1) 5-fluorouracil inibisce la timidilato sintetasi inibendo la metilazione dellrsquoacido desossiuridilico ad acido timidilico e quindi interferendo con la sintesi di DNA

2) Floxuridine

3) Cytosine arabinoside

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 27: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

BJU Int 2011 Jul108(2)168-79 doi 101111j1464-410X201110341x

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinomaShelley MD Cleves A Wilt TJ Mason MD

Cochrane Urological Cancers Unit Velindre NHS Trust Cardiff Cardiff UK mikeshelleywalesnhsukAbstract

OBJECTIVEbull To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer

CONCLUSIONS

bull Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer

bull Gemcitabine may be considered an alternative regime to MVAC

bull Gemcitabine Carboplatin should be considered for patients unfit for cisplatin-based therapy

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 28: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

ANTIMITOTICI

A questa categoria appartengono

1) Tassani

2) Alcaloidi della Vinca

Sito di azione degli antimitotici

Paclitaxel Vincristine

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 29: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Il Paclitaxel egrave un inibitore della mitosi cellulare usato in chemioterapia Ersquo

stato scoperto nel 1967 quando venne isolato da un albero secolare del

pacifico il Taxus brevifolia ed egrave stato sviluppato commercialmente dalla

Bristol-Myers Squibb (BMS) con il nome di paclitaxel

Il paclitaxel interferisce con la normale rottura dei microtubuli

stabilizzando queste strutture

Viene distrutta perciograve la capacitagrave cellulare di usare il citoscheletro in

maniera flessibile legandosi alla subunitagrave beta della tubulina che

costituisce lrsquounitagrave funzionale dei microtubuli stabilizzando lrsquointera

struttura

Meccanismo di Azione

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 30: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

microtuboli

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 31: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

I microtubuli

bull Sono organuli citoplasmatici presenti in tutte le cellule Appaiono al ME come strutture cilindriche cave con un diametro di 25 nm ed uno interno di 15 nm

bull In sezione longitudinale i microtubuli appaiono come bastoncini di lunghezza variabile che puograve raggiungere 20-60 μm

bull La parete dei microtubuli egrave composta da una serie di unitagrave sferoidali ordinate rigidamente di 4 nm Ogni subunitagrave corrisponde ad una molecola di tubulina

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 32: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

I microtubuli

bull La tubulina egrave un dimero di pm 110000 formato da due subunitagrave di sequenza amminoacidica simile chiamate tubulina α e tubulina szlig

bull I dimeri di tubulina polimerizzano a formare lunghe catene chiamate protofilamenti

bull Nella cellula i protofilamenti sono assemblati a gruppi di tredici in una struttura che nel complesso forma il microtubulo

bull I protofilamenti si avvolgono a spirale di passo sinistrorso e decorrono paralleli tra di loro intorno allasse del microtubulo

Citologia BCM BU

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 33: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Il Paclitaxel egrave utilizzato per trattare pazienti con

Cancro al polmoneCancro alle ovaieCancro della mammellaSarcoma di Kaposi

Il sarcoma di caposi egrave caratterizzato da una crescita anormale dei vasi sanguigni che producono lesioni cutanee che possono avvenire anche internamente

Il Paclitaxel egrave usato anche nel prevenire la ristenosi

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 34: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Lancet 2009 Oct 17374(9698)1371-82 Epub 2009 Sep 28Ovarian cancerHennessy BT Coleman RL Markman MDepartment of Gynecologic Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

AbstractThe standard initial management of epithelial ovarian cancer consists of surgical staging operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel

Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes However 75 of patients present with advanced (stage III or IV) disease and although more than 80 of these women benefit from first-line therapy tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis Second-line treatments can improve survival and quality of life but are not curative Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 35: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Effetti collaterali del PACLITAXEL

I piugrave comuni effetti collaterali sono nausea e vomito perdita dellrsquoappetito cambiamento del gusto dolore delle articolazioni che dura diversi giorni formicolio

alle estremitagrave

Effetti collaterali piugrave gravi sono sanguinamento nel sito di iniezione febbre tosse respiro affannato

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 36: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

ALCALOIDI DI ORIGINE VEGETALE

Meccanismo di AzioneLa tubulina egrave una proteina strutturale che polimerizza formando i microtubuli Il citoscheletro egrave costituito da

microtubuli La vincristina lega i dimeri di tubulina inibendo lrsquoassemblaggio strutturale di questi arrestando la

mitosi in metafase Gli alcaloidi della vinca perciograve agiscono rapidamente in cellule che si dividono quali

quelle cancerose ma anche in quelle dellrsquoepitelio intestinale e midollari

Gli alcaloidi della vinca sono Vincristina Vinblastina

La vincristina egrave un alcaloide della Catharanthus roseus originariamente chiamata Vinca rosea Ersquo un inibitore della mitosi cellulare ed egrave usata nella chemioterapia

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 37: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

CA Cancer J Clin 2010 Nov-Dec60(6)393-408 Epub 2010 Oct 28

Improving outcomes for patients with diffuse large B-cell lymphomaFlowers CR Sinha R Vose JM

Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA 30322 USA BarbaraCopelandemoryhealthcareorgAbstractDiffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world Until the mid 1990s the incidence of DLBCL increased in both sexes across racial categories and across all age groups except the very young the etiology of most cases remains unknown DLBCL is associated with an aggressive natural history but it can be cured with combination chemotherapy regimens like cyclophosphamide doxorubicin vincristine and prednisone (CHOP) which has been the mainstay of therapy for several decades Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses and the addition of the monoclonal antibody rituximab to CHOP has markedly improved outcomes Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 38: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

ANTIBIOTICI ANTITUMORALI

Tra gli antibiotici antitumorali sono di tre classi

1) Antracicline (Doxorubicina conosciuta anche come Adriamicina)

2) Antracenedioni (Mitoxantrone)

3) Streptomicine (Actinomicina Bleomicina Mitomicina)

Meccanismo di Azione

Lrsquoesatto meccanismo dellrsquo azione antitumorale della doxorubicina egrave complesso e ancora non ben conosciuto Comunque si pensa che possa intercalarsi nel DNA inibendo la topoisomerasi II la quale apre il DNA per la trascrizione

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 39: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Uso clinico

La doxorubicina egrave comunemente usata per trattare la leucemia il linfoma di Hodgkin cancro alla vescica alla

mammella allo stomaco ai polmoni alle ovaie alla tiroide nel sarcoma di tessuti molli etc

I regimi classici con la doxorubicina sono

1)Doxorubicina + ciclofosfamide + adriamicina

2)Adriamicina + bleomicina + vinblastina + dacarbazide

3)5-fluorouracile + adriamicina + ciclofosfamide

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 40: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Expert Rev Anticancer Ther 2008 Dec8(12)1859-69

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancerStavridi F Palmieri C

Department of Medical Oncology St Georges Hospital Blackshaw Road London SW18 0QT UK

Abstract

Anthracyclines including doxorubicin are the mainstay of therapy for breast cancer However doxorubicin can cause dose-dependent cardiotoxicity limiting the cumulative dose Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues Non-pegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity with anti-tumor responses comparable to those of conventional doxorubicin The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity while allowing a higher cumulative dose

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 41: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Tumori 2009 Jul-Aug95(4)422-6Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer a retrospective analysis

Livi L Meattini I Cardillo Cde L Mangoni M Greto D Petrucci A Rampini A Bruni A Galardi A Cataliotti L Biti G

Abstract

AIMS AND BACKGROUND Anthracyclines such as doxorubicin play a central role in the management of advanced breast cancer Unfortunately the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure In order to limit anthracycline-related cardiotoxicity liposomal formulations of doxorubicin have been developed This retrospective analysis evaluated the experience obtained with non-pegylated liposomal doxorubicin as first-line therapy in 34 patients with metastatic breast cancer

CONCLUSIONS Our results support the use of non-pegylated liposomal doxorubicin as an alternative to conventional doxorubicin formulations in combination regimens for the first-line therapy of metastatic breast cancer

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 42: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

INIBITORI DELLE TOPOISOMERASI

1) Camptotecine (Topotecano e irinotecano)

2) Podofillotossine (Etoposide)

La camptotecina egrave un alcaloide citotossico il quale inibisce la topoisomerasi I Ersquo stata scoperta nel 1966 dalla corteccia di un albero la Camptotheca acuminata nativo della Cina Ha una bassa solubilitagrave percui i chimici farmaceutici hanno prodotto due nuove molecole analoghe della camptotecina e piugrave solubili quali il topotecano e lrsquoirinotecano

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 43: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

A) La Topoisomerases I si lega alla doppia elica del DNA e si lega in modo covalente al terminale 3rsquo della rottura della catena Tutte le altre topoisomerasi si legano alla porzione 5rsquo della catena rotta del DNA Questi complessi sono stabilizzati selettivamente dalla camptotecina

B) Sito catalitico della topoisomerasi I Residuo catalitico della tirosina porta lrsquoattacco nucleofilico e rottura del legame estere fosforico presente nel DNA

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 44: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

The clinical effectiveness and cost-effectiveness oftopotecan for small cell lung cancer a systematicreview and economic evaluationE Loveman J Jones D Hartwell A Bird P Harris K Welch and A CleggSouthampton Health Technology Assessments Centre (SHTAC) UK

Conclusions Topotecan appeared to be better than Best Supporting Care alone in terms of improved survival and was as effective as CAV [cyclophosphamide Adriamycin (doxorubicin) and vincristine] and less favourable than iv amrubicin in terms of response Oral topotecan and iv topotecan were similar in efficacy Topotecan offers additional benefit over BSC but at increased cost ICERs for iv topotecan compared with BSC were high and suggest that it is unlikely to be a cost-effective option The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective Further research into the QoL of patients with relapsed small cell lung cancer (SCLC) could identify the impacts of disease progression and treatment response

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 45: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

ANTICORPI MONOCLONALI

Sono una classe di farmaci in grande sviluppo nella terapia antitumorale Sono molto specifici in quanto di legano ad anticorpi presenti sulle membrane cellulari di cellule tumorali

Il trastuzumab egrave un anticorpo monoclonale umanizzato che agisce al recettore Her 2 Questo tipo di recettore egrave altamente espresso nel tumore della mammella Ersquo somministrato una volta alla settimana o ogni tre settimane per infusione endovenosa per 30-90 minuti

Alemtuzumab It is used to treat patients with chronic lymphocytic leukaemia (CLL) a cancer of the lymphocytes

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 46: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

1) Murine (muro-ab) (100 di origine di topo)Es Muromonab

2) Chimeric (-ximab) (33 di origine di topo)Es Rituximab

3) Humanized (-xumab -zumab) (5-10 di origine di topo)EsAlemtuzumab

4) Human (-mumab) (0 di origine di topo)EsAdalimumab

Nomenclatura degli anticorpi monoclonali in terapia

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

  • Slide 1
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  • I microtubuli
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Page 47: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Struttura di un anticorpo

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 48: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Struttura degli anticorpi

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 49: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

La famiglia delle immunoglobuline

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
  • Slide 38
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Page 50: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

The first type of antibody classification is Immunoglobulin A (IgA) which protects mucosal surfaces with a fluid like secretion (Vedhara amp Irwin 2005) IgA is found in serum mucus saliva tears sweat and milk and has also been associated with being transferred to an unborn child (passive immunity) and can also protect the child after birth for several months This time frame can be further increased when the mother breast-feeds ( Niers Stasse-Wolthuis Rombouts amp Rijkers 2007) A second type of antibody classification is Immunoglobulin E (IgE) which triggers the release of histamines by attaching to antigens basophils and mast cells ( Vedhara amp Irwin 2005) IgE does not make up a very large portion of antigens but it is responsible for reactions resulting in hives asthma and hayfever as examples (Paustian amp Roberts 2005) A third type of antibody classification is Immunoglobulin M (IgM) which forms antibody-antigens processed by the liver and stimulates complement-mediated lysis (Vedhara amp Irwin 2005) IgM makes up about 10 of the total antibodies and it is very important in the initial phases of an illness to stop the spreading of the pathogen ( Paustian amp Roberts 2005) A fourth type of antibody classification is Immunoglobulin G (IgG) which allows for the consumption of pathogens such as bacteria by coating them so that macrophages and neutrophils will be able to recognize them as pathogens (Vedhara amp Irwin 2005) IgG is the largest classification of circulating antibodies ( Paustian amp Roberts 2005) The fifth type of antibody classification is Immunoglobulin D (IgD) which is lacking in enough research to clearly understand its functions (Vedhara amp Irwin 2005) This antibody located on the surface of B-lymphocytes (Paustian amp Roberts 2005) Currently there are research studies being conducted on immature IgD antibodies to transfer them to becoming mature B cells in an effort to try and gain further understanding of the actual function IgD antibodies (Koelsch et al 2007)

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 51: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Am J Transl Res 20113(3)269-274

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
  • Slide 38
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Page 52: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Cellule contenenti una forte sovraespressione di HER-2neu mostrano una migliore inibizione della crescita per effetto dei trattamenti chemioterapici rispetto a quella ottenuta nei sistemi cellulari con piugrave basso livello di espressione

Herneu

LrsquoHER2neu (conosciuto anche come ErbB-2) sta ad indicare Human Epidermal growth factor Receptor 2 ed egrave una proteina ad alta aggressivitagrave nel cancro della mammella Ersquo un membro della famiglia proteica degli ErbB conosciuta piugrave come epidermal growth factor receptor family HER2neu egrave anche conosciuta come CD340 (cluster of differentiation 340) e p185 Ersquo codificata nel gene ERBB2

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 53: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

The last decade has witnessed an increasing number of biologic markers of breast neoplasms One of the markers with probable prognostic significance is over-expression of the HER-2neu oncogene within the tumor Although HER-2neu over-expression has been shown to correlate with a poor prognosis in invasive breast cancer little information is available on the relationship between its over-expression and the outcome of patients with DCIS Previous studies haveindeed demonstrated that HER-2neu expression correlates with aggressive histologic features in DCIS but the prognostic significance of HER-2neu expression in the clinical setting has yet to be determined

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 54: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

111In-Trastuzumab Fab (111In-humAb4D5-8 Fab) is formed by the conjugation of 111In via the bifunctional chelate diethylenetriamine pentaacetic acid (DTPA) with the Fab fragment of the recombinant humanized monoclonal antibody (MAb) against the antigen of human epidermal growth factor receptor 2 (HER2) 111In-Trastuzumab Fab has been developed for imaging of human breast cancer (1-3)

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 55: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Meccanismo di Azione

Lrsquoaumento del numero dei recettore HER2neu (ERB2) avviene nel

20-30 dei casi di tumore alla mammella nei primi stadi della

malattia Questo recettore attiva intracellularmente una via molto

importante che egrave quella della PI3KAkt Questa via egrave associata ai

segnali di mitogenesi coinvolgendo la via della MAPKinasi Nelle

cellule cancerose il recettore HER2neu sono trasmessi

costitutivamente promuovendo lrsquoinvasione la sopravvivenza e

lrsquoangiogenesi cellulare Le cellule tumorali trattate con

trastuzumab si arrestano in fase G1

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 56: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Meccanismo di Resistenza

Il primo meccanismo di resistenza egrave quello dovuto alla induzione di p27kip1 un inibitore del cdk2 e della proliferazione cellulare che rimane nel citoplasma invece di traslocare nel nucleo Questo egrave causato dalla fosforilazione della Akt

Meta-analysis of all available studies based on 12 months of

trastuzumab showed that there was a statistically significant 30

relative improvement in overall survival using the 3-weekly

regimen

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 57: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

EFFETTI TOSSICI DEI FARMACI ANTITUMORALI

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 58: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

INIBITORI DEI FATTORI DI CRESCITA

Erlotinib

LrsquoErlotinib egrave un farmaco usato nel trattamento del cancro al polmone a non piccole cellule cancro pancreatico e altri tipi di cancro

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 59: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Pharmgenomics Pers Med 2013 Aug 5657-62Bosutinib a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Rassi FE Khoury HJDivision of Hematology Department of Hematology and Medical Oncology the Winship Cancer Institute at Emory University Atlanta Georgia USA

AbstractBosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia

Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia especially in the chronic phase with resistance or intolerance to prior tyrosine kinase inhibitors

Bosutinib has distinct but manageable adverse events In the absence of T315I and V299L mutations there are no absolute contraindications for the use of bosutinib in this patient population

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 60: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Mutations

Mutations in the tyrosine kinase inhibitor binding site of BCRABL is another important mechanism of drug resistance The kinase domain mutation frequency is 23 in naive CML patients 40-60 of CML patients under prolonged imatinib exposure that have clinical resistance harbour BCR-ABL kinase domain mutations Point mutations were observed in approximately 35-70 of patients displaying imatinib resistance either spontaneously or through the evolutionary pressure of imatinib If mutations are detected prior to or early after administration of imatinib treatment they generally predict the clinical imatinib-resistance and progression

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 61: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Walker A motif also known as the Walker loop or P-loop (phosphate-binding loop) is a motif in proteins The motif has the pattern GXXXXGK(TS) where G K T and S denote glycine lysine threonine and serine residues respectively and X denotes any amino acid It is an ATP or GTP binding motif found in many nucleotide-bindingproteins

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 62: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

LrsquoEGFR (epidermal growth factor receptor) il recettore per il fattore di crescita epiteliale egrave presente sulla superficie cellulare Per la trasmissione del segnale due molecole di EGFR si debbono legare formando un dimero Attraverso lrsquouso di ATP questei due recettori si fosforilano e questa autofosforilazione porta ad una modificazione strutturale facendo partire tutta una cascata di eventi che portano lrsquoinformazione a livello nucleare per la replicazione cellulare

Lrsquo HER2neu (anche conosciuto come ErbB-2 che significa Epidermal growth factor Receptor 2) egrave una proteina con alta aggressivitagrave nel cancro della mammella HER2neu viene oggi codificato come CD340 e p185

Il fattore di crescita epiteliale

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 63: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Ras= Rat Sarcoma

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 64: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Biochem Soc Trans 2013 Aug41(4)1042-7 Regulation of Janus kinases by SOCS proteinsKershaw NJ Murphy JM Lucet IS Nicola NA Babon JJDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC 3800 Australia

AbstractJAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines However aberrant andor prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels Primarily this is achieved by (i) ensuring that the catalytic domain is switched off under basal conditions and (ii) inhibiting the activity of JAK after it has been switched on Whereas the first mode of inhibition is mediated by JAKs own pseudokinase domain as well as the action of phosphatases the second is achieved by the action of the SOCS (suppressor of cytokine signalling) proteins negative-feedbackinhibitors of JAK-mediated signalling The present review focuses on the mode of action of SOCS1 and SOCS3 the two most potent JAKinhibitors

Janus= the god of beginnings and transitions also of gates doors passages endings and time

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 65: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Figure 1 Regulation of JAKSTAT signalling by SOCS3Schematic diagram of cytokine-induced JAKSTAT signalling SOCS proteins are targets for STAT-induced upregulation whereupon they inhibit signalling forming a negative feedback loop The two most potent members of the SOCS family SOCS1 and SOCS3 act by directly inhibiting the catalytic domain (JH1 domain) of JAK The boxed area indicates the ternary complex structure solved in and shown in the inset Inset the crystal structure of SOCS3 bound to JAK2 and a fragment of the IL-6 receptor (gp130 chain) PDB 4GL9 Figure is reproduced with kind permission from

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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Page 66: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

In biologia molecolare le chinasi regolate da segnali extracellulari (ERKs) dette anche MAP-chinasi sono largamente espresso a livello intracellulare dove sono coinvolte in funzioni quali la regolazione della meiosi mitosi e funzioni postmitotiche in cellule differenziate

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 67: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

LrsquoErlotinib egrave stato mostrato essere un forte inibitore dellrsquoattivitagrave dellrsquoenzima JAK2V617F Il JAK2V617F egrave una mutazione dellrsquoenzima tirosin chinasi ed egrave trovata in larga quantitagrave in pazienti con policitemia vera e in pazienti con mielofibrosi e trombocitopenia Studi recenti suggeriscono che lrsquoerlotinib puograve essere usato per il trattamento di malattie mieloproliferative e nella policitemia vera positiva al JAK2V617F

Meccanismo di Azione

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 68: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Anticancer Res 2010 Apr30(4)1301-10Erlotinib in the treatment of non-small cell lung cancer current status and future developmentsGridelli C Maione P Bareschino MA Schettino C Sacco PC Ambrosio R Barbato V Falanga M Rossi ADivision of Medical Oncology SG Moscati Hospital Contrada Amoretta Avellino Italy cgridelliliberoitAbstractErlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) Currently erlotinib at a standard oral daily dose of 150 mg is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients however it is being investigated in all stages of NSCLC Erlotinib is well tolerated with common toxicities including rash and diarrhoea The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified An important step has been made in the molecular characterization of potentially sensitive NSCLC patients In fact we have learned that activation somatic EGFR gene mutations within the tyrosine kinase domain are associated with a high possibility of a long lasting therapeutic response to erlotinib The present review discusses the role of erlotinib in the treatment of NSCLC

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 69: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

The pharmacokinetic profile of erlotinib a lipophilic drug with poor solubility in water andmethanol has been extensively studied in adults After oral administration erlotinib exhibitedapproximately 60 bioavailability with administration with food enhancing bioavailabilityto upwards of 100 Erlotinib was extensively bound to plasma proteins (95) and wassubject to extensive first-pass hepatic metabolism via the cytochrome P450 3A4 enzymeMetabolism produced several metabolites including the active metabolite O-desmethylerlotinib (OSI-420) and elimination occurs primarily via biliary excretion (63 feces vs 13urine) Maximum concentration of the drug (Cmax) was achieved 2ndash4 hours after doseadministration in adult patients with advanced malignant disease with a half-life ranging from10ndash36 hours The area under the curve (AUC) for erlotinib exhibited inter-patient variabilityand showed a non-linear dose relationship that has been described in several articles and studiesof adult cancer patients

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 70: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Effetti Collaterali degli Inibitori della tirosin kinasi

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 71: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

SummaryErlotinib a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved by FDA for patients with pancreatic cancer and non-small cell lung cancer Skin rash is a well-known side effect related with all EGFR blocking agents It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival There is scant data reporting bacteremia secondary to severe erlotinib skin toxicity In this letter we report a case that developed systemic bacteremia while on erlotinib for treatment of advanced pancreatic cancer due to development of severe rash This case underlines the significance of potential severesystemic infection associated with erlotinib Previously there are many reports describing various skin toxicity manifestation however this is the second case in English literature which had systemic Staphylococcus aureus bacteremia arising from erlotinib skin toxicity Monitor patients closely after starting EGFR blocking agents and initiate immediate skin care based on general guideline are highly recommended

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 72: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Over the last years new agents have been introduced for the treatment of metastatic colorectal cancer the main objective being to prolong patient survival One of these agents is bevacizumab (Avastin Genetech Inc) a monoclonal antibody a diffusible endothelial-specific mitogen and an antibody to vascular endothelial growth factor (VEGF) VEGF is a secreted ligand that binds to specific receptors expressed by angioblasts and endothelial cells

The VEGF receptor (VEGFR) family ligands VEGF-1 and VEGF-2 are biologically related to angiogenesis and VEGF-c and D-VEGFR-3 are associated with lymphangiogenesis Tumor angiogenesis is complex in that many cell types and factors are involved ie such as platelet-derived growth factor b-fibroblast growth factor VEGFA HGF TGFa and EGF The characteristics of the tumor and its environment promote VEGF expression VEGF is overexpressed in a good number of human malignancies and it is considered to be an important regulator of physiologic and pathologic angiogenesis

The vascular endothelial growth factor (VEGF)

Oncology 201078376ndash381

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 73: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

Panitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 74: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.

FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer It is made up of the following drugsFOL ndash folinic acid (leucovorin) a vitamin B derivative used as a rescue drug for high doses of the drug methotrexate and that modulatespotentiatesreduces the side effects of fluorouracilF ndash fluorouracil (5-FU) a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis andIRI ndash irinotecan (Camptosar) a topoisomerase inhibitor which prevents DNA from uncoiling and duplicating

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer made up of the drugsFOLndash Folinic acid (leucovorin)F ndash Fluorouracil (5-FU)OX ndash Oxaliplatin (Eloxatin)[1]

Regimi Terapeutici

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  • I microtubuli
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Page 75: ANTITUMORALI Il cancro è una crescita incontrollata di cellule spesso con comportamento maligno, invasivo e metastatico. Poiche le cellule tumorali continuano.
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  • I microtubuli
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