Fumo di sigaretta e tumori Strategie di prevenzione

Fumo di sigaretta e tumori. Strategie di prevenzione Silvio De Flora Dipartimento di Scienze della Salute Università degli Studi di Genova GE NUEN SE ATHE NAE UM Gd. L SIt. I Prevenzione Tumori / Screening Oncologici

MAINSTREAM SMOKE SIDESTREAM SMOKE ENVIRONMENTAL CIGARETTE SMOKE (ECS)

CIGARETTE SMOKE AND CANCER Evidence for a causal association with the following cancers Respiratory system Digestive system Nasal cavity and paranasal sinuses Oral cavity Naso-, oro-, and hypopharynx Oesophagus Larynx Stomach Lung (90%) Colon-rectum Urinary tract Kidney pelvis Liver Pancreas Bladder Reproductive tract Ureter Ovary Haematopoietic system Uterine cervix Myeloid leukemia IARC Vol. 83, 2004; IARC Vol. 100 E, 2012

DEATHS ATTRIBUTABLE TO TOBACCO SMOKE TOTAL TUMORS 30% LUNG TUMORS 85 -90% AERODIGESTIVE TRACT TUMORS 50– 70% synergism with alcohol CARDIOVASCULAR DISEASES 30% synergism with other risk factors COPD 75% Italy EU USA 90, 000 deaths / year 650, 000 deaths / year 430, 000 deaths / year

Lung and stomach cancers in Italy MALES Deaths per 100, 000 100 90 80 70 60 50 40 FEMALES CRUDE DATA 30 20 100 90 80 70 60 50 40 AGE-STANDARDIZED DATA 30 20 10 0 19 1 2 1 1 1 1 1 2 1 1 30 940 950 960 970 980 990 000 930 940 950 960 970 980 990 000 Year

GROWTH OF THE NEOPLASTIC MASS Cell divisions 0 5 10 15 20 25 30 35 40 No. of cells 10 0 CARCINOGENESIS PROCESS Weight (g) 10 -9 10 1 10 -8 10 2 10 -7 10 3 10 -6 10 4 10 -5 10 -4 10 6 10 -3 10 7 10 -2 8 -1 10 10 10 9 10 0 1010 10 1 1011 10 2 10 12 3 10 TOXICOKINETIKS AND METABOLISM DNA DAMAGE AND REPAIR INITIATION (days - weeks) Exposure dose STOP Pharmacologic dose Cellular dose Target dose Molecular dose PRIMARY PREVENTION PROMOTION (years - decades) BENIGN TUMOR PROGRESSION (~ 1 year) CANCER INVASION NEOPLASTIC MASS SECONDARY PREVENTION C H E M O P R E V E N T I O N THERAPY REHABILITATION METASTASIS TERTIARY PREVENTION S. De Flora et al. , Mutat. Res. 480 -481, 9 -22, 2001

PREVENTION OF LUNG TUMORS IN MICE NUMBER OF TUMORS/MOUSE 0. 35 11. 06 1. 95 CONTROLS (STANDARD DIET) URETHANE (DIET WITH NAC 0. 2%) S. De Flora et al. , Cancer Lett. 32, 235 -241, 1986

PASSIVE SMOKING IN MUTANT MICE P 53 S. De Flora et al. Molecular alterations and lung tumors in P 53 mutant mice exposed to cigarette smoke. Cancer Res. 63, 793– 800, 2003 A. Izzotti et al. Gene expression in the lung of P 53 mutant mice exposed to cigarette smoke. Cancer Res. 64, 8566– 72, 2004 Fhit F. D’Agostini et al. Early loss of Fhit in the respiratory tract of rodents exposed to environmental smoke. Cancer Res. 66, 3936– 41, 2006 S. De Flora et al. Molecular alterations induced by cigarette smoke in mice heterozygous for Fhit. Cancer Res. 67, 1001– 6, 2007 R. Balansky et al. Influence of Fhit on benzo(a)pyrene induced tumors and alopecia in mice. PNAS 103, 7823– 8, 2006

GENOMIC CHANGES IN MOUSE LUNG AT BIRTH A. Izzotti et al. , Mutat. Res. (Rev. Genetic Toxicol. ), 544, 441 -449, 2003 Lung of newborn mice / fetuses UNTREATED PREGNANT MICE NAC–TREATED PREGNANT MICE 8 -oxo-d. Guo DNA adducts 1. 9 5. 0 P < 0. 05 P < 0. 001 0. 9 NS 2. 0 NS Expression of 746 genes

CHEMOPREVENTION STUDIES IN SWISS H MICE EXPOSED TO MCS Chemopreventive agents MCS Birth Weaning Hyperplasia of alveolar epithelium Small cell carcinoma 4 months 7. 5 months Systemic genotoxicity Tumors Papillary hyperplasia of bronchial epithelium Adenocarcinomatous and small cell areas Adenoma Carcinoma in situ Adenosquamous carcinoma Low differentiated carcinoma

DIETARY AND PHARMACOLOGICAL AGENTS THAT HAVE BEEN TESTED FOR THE ABILITY TO INTERFERE IN CIGARETTE SMOKE CARCINOGENESIS (S. De Flora et al. , Trends Pharmacol. Sci. 37, 120 -142, 2016) Natural agents Phenethyl Isothiocyanate Blackberry Strawberry Ascorbic acid Myo-inositol N-Acetylcysteine Antiinflammatory drugs Budesonide Antidiabetic drugs Metformin Aspirin Naproxen Licofelone Pioglitazone Anticancer drugs Vorinostat Lapatinib Bexarotene Celecoxib

DISEASES DECODING THE BLACK BOX S RS YEA RISK FACTORS EKS DA YS E -W EXPOSURE MARKERS Metabolites In excreta Mutagenicity of escreta DE CA E -D EARLY BIOLOGICAL DAMAGE BIOLOGICALLY EFFECTIVE DOSE Metabolic alterations DNA damage and repair Protein adducts Cytogenetic effects DNA adducts Activation of oncogenes 8 -oxo-d. G Deletion or mutation of oncosuppressor genes Effects on proliferation, differentiation, apoptosis, etc. Multigene expression micro. RNA profiles Proteomic profiles

THE ICEBERG OF CHRONIC DEGENERATIVE DISEASES DIAGNOSIS CARDIOVASCULAR DISEASES THERAPY COPD CANCER EPIDEMIOLOGY PREVENTION RISK FACTORS AND PROTECTIVE FACTORS

EXPRESSION OF 4858 GENES IN RAT LUNG A. Izzotti et al. , Mutat. Res. 591, 212– 223, 2005 SMOKE-FREE RATS SHAM NAC OPZ 5, 6 -BF + NAC PEITC SMOKE-EXPOSED RATS I 3 C PEITC + I 3 C ECS OPZ NAC 5, 6 -BF OPZ + NAC I 3 C PEITC + I 3 C PEITC

EFFECT OF ENVIRONMENTAL CIGARETTE SMOKE AND CHEMOPREVENTIVES ON mi. RNA EXPRESSION IN RAT LUNG 0. 6 PCA component 2 0. 5 ECS + PEITC + I 3 C 0. 4 ECS + OPZ + NAC 0. 3 ECS + PEITC 0. 2 ECS + NAC ECS + I 3 C ECS + OPZ 0. 1 ECS + BF 0 NAC -0. 1 BF SHAM NAC + OPZ PEITC -0. 2 OPZ -0. 4 -0. 3 PEITC + I 3 C -0. 2 -0. 1 0. 2 0. 3 0. 4 0. 5 0. 6 0. 7 0. 8 PCA component 1 A. Izzotti et al, Cancer Prev. Res. 3, 62– 72, 2010

PHARMACOGENOMICS / NUTRIGENOMICS OF CHEMOPREVENTIVE AGENTS 2. 4 2. 0 before NAC 6 months after NAC 1. 6 MN (‰) 1. 2 * ** ** 0. 8 0. 4 0 All subjects Fast Slow NAT 2 + Null GSTM 1