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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
DNA ADDUCTS IN THE LUNGS OF RATS
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
DNA ADDUCTS IN THE LUNGS OF RATS
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