Master Catania (7 Modulo

7/27/2019 Master Catania (7 Modulo

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PREVENZIONE PRIMARIA

DEI TUMORI DI ORIGINE AMBIENTALE


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PREVENZIONE PRIMARIA DEI TUMORI

METODI

UOMO: epidemiologia analitica, epidemiologia

molecolare,biomonitoraggio, trials clinici

ANIMALI DA LABORATORIO: valutazione di

biomarcatori intermedi, studi di cancerogenicit

SISTEMIIN VITRO: tests a breve termine


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TEST DI AMES

Ceppi di Salmonella typhimuriumIstidina-richiedenti

+ frazioni post-mitocondriali (S9)di fegato di ratto


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Controlli Fumo Fumo + S9


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ControlliFumo + S9+ inibitoreFumo + S9


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PREVENZIONE PRIMARIA DEI TUMORI

CONTROLLO DEL RISCHIO

VALUTAZIONE DEL RISCHIOGENOTOSSICO E CANCEROGENO

CHEMIOPREVENZIONE

VALUTAZIONE DEGLI EFFETTIE MECCANISMI PROTETTIVI

REGOLAMENTI

Controllo dei

fattori di rischio

ambientali

EDUCAZIONESANITARIA

Fattori di rischiolegati allo stile di

vita

DIETAPopolazione

generale

FARMACI

Individui ad

alto rischio

METODI

UOMO: epidemiologia analitica, epidemiologia

molecolare, biomonitoraggio, trials clinici

ANIMALI DA LABORATORIO: valutazione di

biomarcatori intermedi, studi di cancerogenicit

SISTEMIIN VITRO: tests a breve termine

MODELLI STRUTTURA ATTIVITA (SAR)


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A

C

F

*

VITAMIN A SOURCE

VITAMIN C SOURCE

FIBER SOURCE

CRUCIFEROUS VEGETABLE


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N-Acetil-L-cisteina (NAC)18- Acido glicirretinico

Aspirina

Calcio

-Carotene e altri carotenoidiDHEA Analogo 8354

2-Difluorometilornitina (DFMO)

N-(4-Idrossifenil)retinamide (4-HPR)

IbuprofeneOltipraz

Piroxicam

Proscar

SulindacTamoxifene

Vitamina D3 e analoghi

Vitamina E

G J. Kelloff and C.W. Boone (Eds.), J. Cell. Biochem. Suppl. 20, 1-303, 1994

PIANO DI SVILUPPO PER GLI AGENTI

CHEMIOPREVENTIVI DEL CANCRONCI/NIH


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PREVENTION OF LUNG TUMORS

IN MICE

NUMBER OF TUMORS/MOUSE

0.35

CONTROLS(STANDARD DIET)

11.06

URETHANE(STANDARD DIET)

1.95

URETHANE(DIET WITH NAC 0.2%)

S. De Flora et al., Cancer Lett. 32, 235-241,1986


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DNA ADDUCTS IN THE LUNGS OF RATS

RECEIVING INTRA-TRACHEAL INSTILLATIONS OF


RECEIVING INTRA-TRACHEAL INSTILLATIONS OF

A. Izzotti, A. Camoirano, F. DAgostini, S. Sciacca, F. De Naro Papa, C.F. Cesarone, S. De FlorCancer Res. 56, 1533-1538, 1996

POLLUTED AIR PARTICULATE EXTRACTSPOLLUTED AIR PARTICULATE EXTRACTS


RECEIVING INTRA-TRACHEAL INSTILLATIONS OFPOLLUTED AIR PARTICULATE EXTRACTS


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NACNAC NAC

URINARY MUTAGENICITY IN A SMOKER AS RELATED TO NAC ADMINISTRATION

1 2 3 4 5 6 7 8 9

Time (days)

Revertants/24hx

103

0

5

10

15

20

25

30

35

S. De Flora et al., J. Cell. Biochem. 58 (Suppl. 22), 33-41,1995


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Angioprevention in multistage tumorigenesis

Epithelium

BasementMembrane

Dermis

Dysplasia(In situ)

Neoplasia

(invasion)

Neoplasia

Metastatic

Dissemination/Extravasation

(metastatic)

Angiogenesis Angiogenesis

Antiangiogenic agents

Normal

Angiogenesis

F. Tosetti et al., FASEB J. 16, 2-14, 2002


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LA NAC INIBISCE LESPRESSIONE DELVEGF IN CELLULE DI SARCOMA DI KAPOSI


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NAC +

VASCOLARIZZAZIONE DI SPUGNE DI MATRIGEL

NAC

T. Cai et al., Lab. Invest. 79, 1151-1159, 1999


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CRESCITA DI SARCOMA DI KAPOSI UMANO IN TOPI NUDI

A. Albini et al., Cancer Res. 61, 8171-8178, 2001

MASCHI

FEMMINE

3) +Volume

deltumore(cm

) 0

0.5

1.0

1.5

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

CONTROLLI

Tempo (giorni)5 10 15 20 25 30

3

+

NAC

5 10 15 20 25 30

FEMMINE

MASCHI


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Treatmentgroup

Tumor weight after 60 daysStatistical significance

mean SE

Controls

A

B

3.09 0.14

NAC p.o. ( + 16 h )12.25 mmol/Kg b.w.

1.77 0.18 P< 0.0001 Vs. A

C1.45 0.12

1.11 0.11

0.73 0.08

P< 0.001

P< 0.0001

P= 0.009P= 0.07

P< 0.0001

P< 0.0001

P< 0.0001

Vs. A

Vs. A

Vs. BVs. C

Vs. A

Vs. B

Vs. C

DOX i.v. ( + 24 h )2 mol/Kg b.w.

NAC ( 72 h )

DOX ( + 24 h )

INHIBITION OF LOCALTUMORS (MELANOMA)IN BLACK MICE

F. DAgostini et al.,

Int. J. Oncol.13, 217-224, 1998

D

NAC ( + 16 h )DOX ( + 24 h )

E


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CHEMOPREVENTION OF CIGARETTE SMOKEINDUCED TUMORSCHEMOPREVENTION OF CIGARETTE SMOKEINDUCED TUMORSR. Balansky et al., Int. J. Cancer 126, 1046-54, 2010R. Balansky et al., Int. J. Cancer 126, 1046-54, 2010

M

F

M+F

M

F

M+F

Sham

MCS

0 10 20 30 40 50 60 70 0 1 2 3 4 5

Incidence (%) Multiplicity (mean SE)

P< 0.1P< 0.05

P< 0.01

P< 0.001

M

F

M+F

M

FM+F

M

F

M+F

MCS + Budesonide

(current smokers)

MCS + PEITC

(current smokers)

MCS + NAC

(current smokers)

M

F

M+F

M

F

M+F

MCS + Budesonide

(exsmokers)

MCS + PEITC

(exsmokers)


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CHEMOPREVENTION OF CIGARETTE SMOKEINDUCEDLUNG ADENOMAS BY NATURAL PRODUCTS

CHEMOPREVENTION OF CIGARETTE SMOKEINDUCEDLUNG ADENOMAS BY NATURAL PRODUCTS

0 5 10 15 20 25 30 0 0.25 0.50 0.75

Incidence (%) Multiplicity (mean SE)

35

M

F

M+FMCS

ShamM

F

M+F

M

FM+FMCS + SB

M

F

M+FMCS + BCB **

**

**

***

*

BCB = black chokeberry SB = strawberry


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UNTREATED

PREGNANTMICE

GENOMIC CHANGES IN MOUSE LUNG AT BIRTH

A. Izzotti et al., Mutat. Res. (Rev. Genetic Toxicol.), 544, 441-449, 2003

DNA adducts Expression of 746 genes8-oxo-dGuo

Lung of newborn mice / fetuses

5.05.01.9

P < 0.05 P < 0.001

2.00.9NS

NS

NACTREATEDPREGNANT

MICE


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UNTREATEDPREGNANTMICE

HYPERPLASIA

OF BLADDER

EPITHELIUM

MICE EXPOSED TO SMOKE AFTER BIRTH

61.1 %

16.7 % 20.4 %

LUNG

EMPHYSEMA

LUNG TUMORS

R. Balansky et al., Carcinogenesis 30, 1398-1401, 2009

NACTREATED

PREGNANTMICE

17.0 % 6.4 % 2.1 %


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SHAM NAC OPZ OPZ

+ NAC

5,6-BF PEITC I3C PEITC

+ I3C

A. Izzotti et al., Mutat. Res. 591, 212223, 2005

SMOKE-FREE MICE

ECS NACOPZ OPZ

+ NAC

5,6-BF PEITCI3C PEITC

+ I3C

SMOKE-EXPOSED MICE

EXPRESSION OF 4858 GENES IN RAT LUNG


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-0.4 -0.3 0.20.10-0.1-0.2 0.80.70.60.50.40.3

0.2

0.1

0

-0.1

-0.2

0.6

0.5

0.4

0.3

ECS + BF

ECS + OPZ ECS + I3C

ECS + NAC

ECS + PEITC

ECS + OPZ + NACECS + PEITC + I3C

SHAM

ECS

NAC

OPZ PEITC + I3C

PEITC

NAC + OPZBFP

CAco

mponent2

PCA component 1

EFFECT OF CIGARETTE SMOKE (ECS) AND CHEMOPREVENTIVE

AGENTS ON miRNA EXPRESSION IN RAT LUNG

A. Izzotti et al, Cancer Prev. Res. 3, 6272, 2010


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PREVENZIONE TERZIARIA

(malati di cancro curati)

INTERVENTO PRECOCE(malati di cancro in fase preclinica o precoce)

PREVENZIONE DELLA PROGRESSIONE(individui affetti da lesioni precancerose)

CHEMIOPREVENZIONE MIRATA(individui ad alto rischio)

INTERVENTO DI SANITA PUBBLICA(soggetti sani nella popolazione)

EFFICACIA

BASSO COSTO

PRATICITA

TOLLERABILITA

REQUISITI

TERAPIA (malati di cancro)

INTERVENTI (Bersagli)

S. De Flora et al., IARC Sci. Publ. No. 139, 1996, pp. 291-301


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PHASE II CHEMOPREVENTION TRIAL

WITH NAC IN DUTCH SMOKERS

PHASE II CHEMOPREVENTION TRIAL

WITH NAC IN DUTCH SMOKERS

F.J. van Schooten et al., Cancer Epidem. Biomarkers Prev. 11, 167-175, 2002

DNA adducts/108 nucleotides

in BAL cells

8oxodGuo/105 nucleotides

in BAL cells

Micronuclei inmouth cells

()

PlaceboPlacebo

NACNAC

T0

T6

T0

T6

6.0 0.7 4.8 0.5 1.2 0.3

5.9 0.7 3.2 0.8 1.0 0.2

6.0 0.9 4.9 0.7 1.3 0.3

4.3 0.8 1.8 0.3 0.9 0.3

Statistically significant as compared to T0


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before NAC

Allsubjects

0

0.4

0.8

1.2

1.6

2.0

2.4

Fast

NAT2

+

GSTM1

6 months after NAC

*MN

()

PHARMACOGENOMICS / NUTRIGENOMICS

OF CHEMOPREVENTIVE AGENTS

NullSlow

****


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ACE inhibitorsBetablockersStatins

DexrazoxaneLCarnitineCoenzyme Q10NAcetylLCysteineGlutathioneErdosteine

SeleniumZincMelatoninFlavonoids and polyphenolsPlatelet antiaggregants

Anthracyclines andanthraquinolones

Capecitabine, Cytarabine,

5FluorouracilPaclitaxel, Vinca alkaloids

Cyclophosphamide

TK Inhibitors (Trastuzumab,Imatinib, Bevacizumab,

Sorafenib, Sunitinib, etc)COX2 inhibitors

Estrogen receptor modulators

Irradiation to the thorax

Mitochondrial dysfunctionApoptosis of cardiomyocytesROS generation

DNA damageEndothelial cell damageAntibody directed cellular cytotoxicityATP blockCell signaling, survival blockFibrosis

HypertensionSinus bradicardiaAtrium-ventricular blockVentricular tachycardiaArrhythmiasThromboembolism

Anticancer drugs Mechanisms of cardiotoxicity Protective agents


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CEREBROVASCOLARI M

F

152,4 (1928)

123,2 (1940)

42,0 72,4%

31,5 74,4%

DECLINO DELLA MORTALIT PER MALATTIE

CRONICO-DEGENERATIVE NEL XX SECOLO IN ITALIA

MALATTIE GENERE MAX (ANNO) 2000 DIMINUZIONE

MORTALIT PER 100.000 (st. per et)

CARDIOVASCOLARI M 273,5 (1963)

F 233,5 (190156)

131,6 51,9%

74,9 67,9%

TUMORI M 196,2 (1987)

F 100,0 (195689)

160,2 18,3%

87,1 12,9%


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ITALY, GENERAL MORTALITY DATA, 19012000

Ratesper100.00

0

0

5

15

25

30

35

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

10

20

ITALY, 1901Population: 33 millionDeaths: 726,000Mortality rate: 22

ITALY, 2000Population: 58 millionDeaths: 560,000Mortality rate: 9.7

ITALY, 2000Population: 58 million

Mortality rate:

Deaths:

22

1,276,000

THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY

S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892897, 2005

Master Catania (7 Modulo

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