DeFlora - Tumori_professionali
Transcription
DeFlora - Tumori_professionali
EPIDEMIOLOGIA E PREVENZIONE DEI TUMORI PROFESSIONALI Silvio De Flora GE NUEN SE ATHE NAE UM Università di Genova Dipartimento di Scienze della Salute Sezione di Igiene e Medicina Preventiva OBIETTIVI Epidemiologia descrittiva Epidemiologia analitica Epidemiologia molecolare Prevenzione primaria, secondaria e terziaria Meccanismi della cancerogenesi Esistono soglie in cancerogenesi ? Conclusioni THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005 ITALY, 1901–2000 (RAW MORTALITY DATA) 1407 Deaths per 100,000 500 INFECTIOUS AND DIGESTIVE ACCIDENTAL TRACT RESPIRATORY DIS. PARASITIC DISEASES DISEASES CAUSES (INCLUDING FLU) 400 EPIDEMIOLOGIA DESCRITTIVA 300 200 100 RESP ACC DIG INF 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005 ITALY, 1901–2000 (RAW MORTALITY DATA) 1407 Deaths per 100,000 500 CARDIOVASCULAR CEREBROVASCULAR CANCER DISEASES 400 CARD 300 CAN 200 CER 100 RESP ACC DIG INF 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 ETA’ E TUMORI EVOLUZIONE DELLA SPERANZA DI VITA ALLA NASCITA ETA’ E MALATTIE CRONICO-DEGENERATIVE THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005 ITALY, 1901–2000 (AGE-STANDARDIZED MORTALITY DATA) Deaths per 100,000 1436 500 CEREBROVASCULAR DISEASES M –72.4% F –74.4% 400 CARDIOVASCULAR DISEASES M –51.9% F –67.9% CANCER 300 M –18.3% F –12.9% CARD 200 1 2 3 CAN CER 100 ACC RESP INF 0 DIG 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 MORTALITA’ PER TUMORI IN ITALIA DATI GREZZI 350 Decessi per 100.000 300 Maschi 250 200 150 Femmine 100 50 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 MORTALITA’ PER TUMORI IN ITALIA DATI STANDARDIZZATI PER ETA’ 350 Decessi per 100.000 300 250 Maschi 200 150 Femmine 100 50 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 DATI DI INCIDENZA DEI TUMORI IN ITALIA Oltre 20 milioni di italiani (36,1% della popolazione) vivono in aree coperte dall’attività dei Registri Tumori (Dati 2011) PRINCIPALI TUMORI IN ITALIA (AIRTUM Working Group, 2009) Maschi Polmone 27.043 23.969 Colon-retto 9.752 29.283 175.449 Prostata 7.460 ˜ 42.000 NA Stomaco 6.244 62.463 7.261 36.273 Femmine Mammella 11.476 38.286 Colon-retto 8.315 19.650 Polmone 7.350 Stomaco 138.314 7.082 4.376 0 472.112 10 16.052 4.583 20 30 Morti nel 2006 (x103) 0 10 24.234 20 30 40 Casi incidenti attesi nel 2010 (x103) 0 100 200 300 400 500 Casi prevalenti stimati (x103) SOPRAVVIVENZA A 5 ANNI PER TUMORE IN ITALIA (2002–2004) DATI AIRTUM 2011 Pancreas 5% Ossa 55% Melanoma cutaneo 85% Mesotelioma 7% Testa e collo 56% Linfoma di Hodgkin 84% Esofago 11% Tratto urinario 57% Sarcoma di Kaposi 85% Vie biliari 13% Colon retto 58% Mammella 87% Polmone 13% Ghiandole salivari 60% Prostata 88% Fegato 14% Linfoma non Hodgkin 60% Tiroide 94% Sistema nervoso 17% Cervice uterina 67% Testicolo 95% Leuc. mieloide acuta 17% Rene 68% Leuc. linfatica acuta 26% Leuc. linfatica cronica 69% Stomaco 29% Pancreas 70% Ovaie 41% Vescica urinaria 76% Mieloma 42% Corpo uterino 78% L. mieloide cronica 49% Intestino tenue 49% TUTTI eccetto t. cutanei non melanoma 56% Diade di Ippocrate AMBIENTE UOMO EPIDEMIOLOGIA MALATTIA INFETTIVA ANALITICA Causa necessaria ma non sufficiente AGENTE EZIOLOGICO FATTORI DI RISCHIO MALATTIE FR 1 M1 MORTI PER TUMORE - RISCHIO ATTRIBUIBILE FR 2 Tabacco 30% M2 Dieta 40% Inattività fisica 2% FR 3 Inquinamento 3% Farmaci <1% FR FR 44 Infezioni 15% Occupazione 3% Radiazioni ionizzanti e luce 6% M3 M4 DIETA, ALIMENTAZIONE E CANCRO FATTORI DI RISCHIO FATTORI PROTETTIVI Dieta ipercalorica Esercizio fisico Dieta iperproteica ? Dieta iperglucidica (carboidrati semplici)? Dieta iperlipidica (< 30% Cal; < 10% a. grassi saturi) Contaminanti naturali (micotossine) Componenti naturali (idrazine, pesticidi naturali) Contaminanti artificiali (pesticidi) Conservanti/additivi/coloranti Precursori di cancerogeni endogeni Inibitori nitrosazione (Vit. C) Eccesso di NaCl Salatura alimenti Conservazione alimenti Affumicatura alimenti a bassa temperatura Abbrustolimento e frittura alimenti Forni a microonde Eccessiva temperatura Vitamine antiossidanti (A, ac. folico, C, E) Elementi chimici (Se, Ca) Clorofillina Vari composti protettivi (crucifere) Fibre indigeribili Prodotti lattiero-caseari fermentati Frutta e verdura, bevande (vino, thé) Tumori del polmone e dello stomaco in Italia MASCHI FEMMINE Decessi per 100.000 100 90 80 70 60 50 40 DATI GREZZI 30 20 10 0 100 90 80 70 60 50 40 DATI STANDARDIZZATI 30 20 10 0 Anno MAINSTREAM SMOKE SIDESTREAM SMOKE ENVIRONMENTAL CIGARETTE SMOKE (ECS) 5000 200 Men Women 4000 Smoking Lung cancer 150 3000 100 Smoking 2000 50 1000 Lung cancer 0 0 1900 1920 1940 1960 Annual lung cancer deaths per 100,000 population Annual per capita consumption of cigarettes INCREASING CONSUMPTION OF CIGARETTES IS FOLLOWED BY A STEEP RISE IN DEATHS FROM LUNG CANCER 1980 Lung cancer deaths in England and Wales show a close correlation with the number of cigarettes smoked in earlier years. Source: J. Cairns. MORTALITA’ PER TUMORI POLMONARI (DATI STANDARDIZZATI PER 100.000) 90 80 UNGHERIA Maschi 70 USA 60 UK 50 ITALIA 40 30 30 GIAPPONE 20 20 10 10 USA Femmine UK UNGHERIA GIAPPONE ITALIA 0 1965-69 70-74 75-79 80-84 85-89 92 0 1965-69 70-74 75-79 80-84 85-89 92 PASSIVE SMOKING IN MUTANT MICE R. Yao et al. K-Ras mutations in lung tumors from P53 mutant mice exposed to cigarette smoke. Exp. Lung Res. 31, 271–281, 2005 S. De Flora et al. Molecular alterations and lung tumors in P53 mutant mice exposed to cigarette smoke. Cancer Res. 63, 793–800, 2003 A. Izzotti et al. Gene expression in the lung of P53 mutant mice exposed to cigarette smoke. Cancer Res. 64, 8566–72, 2004 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-dGuo DNA adducts 1.9 5.0 P < 0.05 P < 0.001 0.9 NS 2.0 NS Expression of 746 genes MICE EXPOSED TO SMOKE AFTER BIRTH LUNG TUMORS UNTREATED PREGNANT MICE LUNG HYPERPLASIA EMPHYSEMA OF BLADDER EPITHELIUM 61.1 % 16.7 % 20.4 % 6.4 % 2.1 % NAC–TREATED PREGNANT MICE 17.0 % NAC - R. Balansky et al., Carcinogenesis 30, 1398-1401, 2009 AsA - R. Balansky et al., CCDT 12, 164-169, 2012 THE PREVENTION OF INFECTION–ASSOCIATED CANCERS (S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011) Pathogen IARC Main asociated cancer Group Hepatitis viruses HBV HCV HDV 1 1 3 4.9% of all cancers Hepatocellular carcinoma 85.5% of all HCCs Hepatocellular carcinoma None Pathogen IARC Group Main asociated cancer 1 3 1 Adult T-cell leukemia/lymphoma Retroviruses HTLV-I HTLV-II HIV-I Papillomaviruses HPV a HPV type 16 a HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 a HPV type 68 1 Cancers at several sites 1 Cervical cancer 5.2% of all cancers 2A Cervical cancer a HPV types 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97 100% of cervix cancers 2B Cervical cancer b HPV type 5 and 8 2B Skin cancer a HPV type 6 and 11 3 None Other b and g HPV types 3 None Polyomaviruses JCV NA MCV NA SV40 NA CNS tumors and colorectal cancer? Skin cancer (Merkel cell carcinoma) Malignant mesothelioma ? HIV-II 2B HERV-K NA Helicobacter pylori Schistosomes S. haematubium S. japonicum S. mansoni None Kaposi’s sarcoma, non-Hdgkin’s lymphoma, Hodgkin’s lymphoma, cervical cancer, anus cancer, conjunctive cancer Kaposi’s sarcoma, non-Hodgkin’s lymphoma Human breast cancer 5.5%Gastric of all cancers cancer, MALT 63.4% of stomach cancers 1 1 2B 3 Urinary bladder cancer Colorectal and liver cancers None Liver flukes Opistorchis viverrini Opistorchis felineus Chlonorchis sinensis 1 3 1 Cholangiocarcinoma None Cholangiocarcinoma Herpesviruses EBV or HHV4 1 KSHV or HHV8 1 Burkitt’s lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppressor-related nonHodgkin’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma Kaposi’s sarcoma, primary effusion lymphoma Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005 UV-R-250 -280 -340 Sunlight Fluorescent lamp FONTI DI ILLUMINAZIONE ARTIFICIALE Halogen lamp ESPOSIZIONE DI TOPI HAIRLESS ALLE LAMPADE ALOGENE CANCEROGENICITA’ CUTANEA DELLE LAMPADE ALOGENE WITHOUT COVER WITH COVER S. De Flora & F. D’Agostini, Nature (London) 356, 569, 1992 Agenti cancerogeni in Lista I del Ministero del Lavoro (G.U. 19/03/2010, n. 65) Polmone Vescica Asbesto, Berillio, (Bis)Clorometiletere, Cadmio, Nickel, Cromo(VI), IPA, TCDD, Radon, Silice, Fumo passivo Ammine aromatiche, IPA Pleura Arsenico, IPA, Radiazioni solari Cute Asbesto, Erionite Sistema emolinfopoietico Nickel, Cromo(VI) Benzene, 1,3-Butadiene, Ossido di etilene, Radiazioni ionizzanti Nasofaringe Linfomi Formaldeide TCDD, HIV Fegato Sarcomi Arsenico, Cloruro di vinile, HBV, HCV TCDD, HIV Cavità nasali e seni paranasali MONITORAGGIO BIOTOSSICOLOGICO DELL’ACQUA Bioindicatori alterati in trote stabulate nel punto C: Mutagenicità della bile (1) Induzione di enzimi microsomiali epatici (2) MONITORAGGIO BIOTOSSICOLOGICO DEI SEDIMENTI A] Iniezione di estratti di sedimenti in trote adulte Eliminazione di metaboliti fluirescenti con la bile (1) Induzione di enzimi microsomiali epatici (2) Induzione dell’attivazione metabolica di un cancerogeno nel fegato(2) B] Esposizione per contatto di larve di trota Effetti citogenetici (micronuclei in Induzione di enzimi microsomiali in estratti eritrociti(3) di larva (2) A FIUME LAMBRO CONTROLLI Indicatori biotossicologici IN ACQUARIO (1) Marcatore di esposizione B C (2) Marcatore di effetto biologico precoce (3) Marcatore di danno genetico FIUME PO MUTAGENICITY OF SEDIMENTS ALONG THE PO RIVER AND GENOTOXICITY BIOMARKERS IN FISH L. Viganò et al., Mutat. Res. 515, 125–134, 2002 ADDOTTI BPA–DNA IN VITRO SPOTS AUTORADIOGRAFICI DOSE–DIPENDENZA Adducts/108 nucleotides 8 7 6 5 4 3 2 1 0 0 50 100 150 200 250 BPA dose (ng/l) A. Izzotti, S. Kanitz , F. D’Agostini, A. Camoirano & S. De Flora, Mutat. Res. 679, 28-32, 2009 FRAMMENTAZIONE DI SPERMATOZOI DI RATTI INDOTTA DA BPA A. Izzotti, S. Kanitz , F. D’Agostini, A. Camoirano & S. De Flora, Mutat. Res. 679, 28-32, 2009 Impianto da 60.000 ton/anno BPA Studi epidemiologici suggeriscono che la qualità e quantità dello sperma umano sono diminuite durante gli ultimi 6 decenni FATTORI PROTETTIVI MALATTIE FP 1 M1 FP 2 M2 FP 3 M3 FP 4 M4 DISEASES DECODING THE BLACK BOX EARLY BIOLOGICAL DAMAGE EPIDEMIOLOGIA MOLECOLARE EXPOSURE MARKERS RISK FACTORS Analysis of metabolites BIOLOGICALLY EFFECTIVE DOSE Metabolic alterations DNA damage and repair Protein adducts Cytogenetic effects Activation of oncogenes DNA adducts 8-oxo-dG Deletion/mutation of oncosuppressor genes Proliferation, differentiation, apoptosis, etc. Mutagenicity of escreta GENOME C G o S lo m e H r n A e m e M d u L b is v y ( t s : 4 : 8 C 4 S ) , MIRNOME TRANSCRIPTOME D e f a u lt I n t e r p r e t a t io n PROTEOME ( s h a m . t x t ) PROTECTIVE FACTORS DISEASES EARLY BIOLOGICAL DAMAGE EXPOSURE MARKERS STOP RISK FACTORS Analysis of metabolites BIOLOGICALLY EFFECTIVE DOSE Metabolic alterations DNA damage and repair Protein adducts Cytogenetic effects Activation of oncogenes DNA adducts 8-oxo-dG Deletion/mutation of oncosuppressor genes Proliferation, differentiation, apoptosis, etc. Mutagenicity of escreta GENOME C G o S lo m e H r n A e m e M d u L b is v y ( t s : 4 : 8 C 4 S ) , MIRNOME TRANSCRIPTOME D e f a u lt I n t e r p r e t a t io n PROTEOME ( s h a m . t x t ) Cigarettes / day 40 30 r = 0.57 P < 0.05 20 10 0 0 50 100 150 200 BPDE-DNA adducts (FU) A. Izzotti et al., Carcinogenesis 12, 1281-1285, 1991 THE 'OMICS TECHNOLOGIES S. De Flora & A. Izzotti, Mutat. Res., 667, 15–26, 2009 DNA mRNA microRNA Proteins GENOME Co lo r e d b SHAM y: v s CS, G e n e L is m t : m u ( 484) De f a u lt I n t e r p r e t a t io n ( sham . t xt ) MIRNOME TRANSCRIPTOME PROTECTIVE FACTORS PROTEOME Chronic degenerative diseases and critical periods of life ENVIRONMENTAL CIGARETTE SMOKE IN RAT LUNG MicroRNA CIGARETTE SMOKE DNA mRNA Proteins 10000 100 10 1 1000 0,1 0,01 0,01 0,1 1 10 100 1000 10000 SHAM SHAM SHAM 126 / 484 miRNAs (26.0%) downregulated by ECS 107 / 4858 genes (2.9%) upregulated by ECS 50 / 518 proteins (9.7%) upregulated by ECS A. Izzotti et al., FASEB J. 23, 806–812, 2009 THE ICEBERG OF CHRONIC DEGENERATIVE DISEASES DIAGNOSIS CARDIOVASCULAR DISEASES THERAPY COPD CANCER EPIDEMIOLOGY PREVENTION RISK FACTORS AND PROTECTIVE FACTORS COMMON PATHOGENETIC MECHANISMS De Flora & D’Agostini, Nature 1992 Stem cell susceptibility Balansky et al, Cancer Res. 1996 Age–related diseases Perinatal vulnerability Cancer Atherosclerosis Degenerative heart diseases DNA damage Epigenetic mechanisms Oxidative stress Chronic inflammation Transplacental damage Genetic predisposition Neurological disorders Skin ageing and alopecia Metabolic syndrome Balansky et al, PNAS 2006 Chronic obstructive pulmonary diseases Eye diseases Diabetes HUMAN ABDOMINAL AORTA WITH ATHEROSCLEROTIC LESIONS Extraction of DNA from smooth muscle cells MOLECULAR EPIDEMIOLOGY OF ATHEROSCLEROSIS S. De Flora et al., FASEB J. 11: 1021-1031, 1997 The levels of 32P postlabelled DNA adducts in the aorta from 85 atherosclerotic patients were significantly correlated with: -Age of patients -Number of cigarettes smoked currently -High blood pressure -Blood triglycerides -Blood cholesterol (total/HDL) -SFS-positive DNA adducts -Oxidative DNA damage (8-OH-dG) 8–oxo–dG DNA ADDUCTS DANNO OSSIDATIVO AL DNA NEL TRABECOLATO OCULARE 8–oxo–dG/105 nucleotidI (A. Izzotti et al., Am. J. Med. 114, 638-646, 2003) 25 20 15 10 5 0 GSTM1 - nulli GSTM1 + Controlli (n = 47) GSTM1 - nulli GSTM1 + Malati di glaucoma (n = 39) DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN S. La Maestra et al., Toxicol. Sci., 123, 471-479 2011 DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN S. La Maestra et al., Toxicol. Sci., 123, 471-479 2011 DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN S. La Maestra et al., Toxicol. Sci., 123, 471-479 2011 PROLIFERATION AND CHRONIC DEGENERATIVE DISEASES DNA damage and repair Oxidative stress Chronic inflammation Epigenetic mechanisms Cancer Atherosclerotic plaque Degenerative diseases of the myocardium Neurodegenerative diseases 1963 1973 2012 I LIVELLI DELLA PREVENZIONE PREVENZIONE PRIMARIA Prevenzione di una malattia in individui sani (prevention of occurrence) STRATEGIE DI PREVENZIONE SECONDARIA PREVENZIONE Diagnosi precoce, possibilmente in fase preclinica, seguita da terapia tempestiva (prevention of progression) PREVENZIONE TERZIARIA Prevenzione delle complicazioni e delle ricadute di una malattia, dopo terapia CRESCITA DELLA MASSA NEOPLASTICA Divisioni cellulari No. Di cellule 0 10 0 10-9 10 1 10-8 2 -7 5 10 10 20 25 30 10-6 4 -5 10 10 5 10-4 10 6 10-3 10 7 10-2 10 8 -1 10 9 10 10 0 10 1 11 10 2 10 12 10 3 1010 35 10 40 10 10 3 10 15 Peso (g) PROCESSO DI CANCEROGENESI Dose espositiva TOSSICOCINETICA E METABOLISMO Dose cellulare DANNO E RIPARO DEL DNA Dose farmacologica Dose bersaglio STRATEGIE DI INTERVENTO Ambiente e stile di vita Dose molecolare INIZIAZIONE (giorni - settimane) PREVENZIONE PRIMARIA PROMOZIONE (anni - decenni) Organismo ospite (chemio prevenzione) TUMORE BENIGNO PROGRESSIONE (~ 1 anno) PREVENZIONE SECONDARIA CANCRO INVASIONE MASSA NEOPLASTICA METASTASI TERAPIA e PREVENZIONE TERZIARIA PREVENZIONE SECONDARIA / SCREENING ONCOLOGICI Razionale e criteri La malattia deve essere un problema di sanità pubblica e coinvolgere un gran numero di persone Esistono lesioni precancerose o stadi precoci della malattia che è possibile diagnosticare Esiste un metodo diagnostico sicuro e di facile esecuzione, non eccessivamente costoso, non invasivo, non dannoso e dotato di elevata performance (sensibilità e specificità) Il trattamento precoce è vantaggioso in termini di riduzione dell’incidenza e/o della mortalità Esistono strutture qualificate in grado di effettuare diagnosi e terapie adeguate Osservatorio Nazionale Screening (ONS) Gruppo Italiano per lo Screening Mammografico (GISMa) Gruppo Italiano per lo Screening Cervicale (GISCi) Gruppo Italiano per lo Screening Colorettale (GISCoR) Questi programmi di screening sono stati individuati come LEA Obiettivi del Ministero della Salute (fine 2007): Copertura di tutto il territorio nazionale per gli screening mammografici (donne di 50–69 anni) e cervicali (donne di 25–64 anni) Invito almeno al 50% della popolazione di 50–69 anni per lo screening colorettale CRESCITA DELLA MASSA NEOPLASTICA Divisioni cellulari 0 5 10 15 20 25 30 No. Di cellule 10 0 40 STOP Dose espositiva Dose farmacologica TOSSICOCINETICA E METABOLISMO Dose cellulare -9 10 10 1 10-8 10 2 10-7 10 3 10-6 10 4 -5 10 5 10 Dose bersaglio DANNO E RIPARO DEL DNA 10 7 10-2 10 8 -1 10 9 10 10 0 10 1 PROMOZIONE (anni - decenni) STOP Organismo ospite (chemio prevenzione) TUMORE BENIGNO PROGRESSIONE (~ 1 anno) 10 2 10 12 10 3 PREVENZIONE SECONDARIA CANCRO INVASIONE 1011 Ambiente e stile di vita PREVENZIONE PRIMARIA 10 10-3 STRATEGIE DI INTERVENTO Dose molecolare INIZIAZIONE (giorni - settimane) -4 10 6 1010 35 Peso (g) PROCESSO DI CANCEROGENESI MASSA NEOPLASTICA METASTASI TERAPIA RIABILITAZIONE PREVENZIONE TERZIARIA A VITAMIN A SOURCE C VITAMIN C SOURCE F FIBER SOURCE * CRUCIFEROUS VEGETABLE NCI/NIH PIANO DI SVILUPPO PER GLI AGENTI CHEMIOPREVENTIVI DEL CANCRO N-Acetil-L-cisteina (NAC) 18b- Acido glicirretinico Aspirina Calcio b-Carotene e altri carotenoidi DHEA Analogo 8354 2-Difluorometilornitina (DFMO) N-(4-Idrossifenil)retinamide (4-HPR) Ibuprofene Oltipraz Piroxicam Proscar Sulindac Tamoxifene Vitamina D3 e analoghi Vitamina E G J. Kelloff and C.W. Boone (Eds.), J. Cell. Biochem. Suppl. 20, 1-303, 1994 MECHANISMS OF CANCER CHEMOPREVENTIVE AGENTS S. De Flora and C. Ramel, Mutat. Res., 202, 285–306, 1988 3. Inhibition of tumor promotion PRIMARY PREVENTION 1. Inhibition of mutation and cancer initiation in the extracellular environment or in nontarget cells 1.1. Inhibition of uptake of mutagens/carcinogens 1.1.1. Inhibition of penetration 1.1.2. Removal from the organism 1.2. Inhibition of the endogenous formation of mutagens and carcinogens 1.2.1. Inhibition of the nitrosation reaction 1.2.2. Modification of the intestinal microbial flora 1.3. Complexation, dilution and/or deactivation of mutagens/carcinogens outside cells 1.3.1. By physical or mechanical means 1.3.2. By chemical reaction 1.3.3. By enzyme–catalyzed reaction 1.4. Favoring absorption of protective agents 1.5. Stimulation of trapping and detoxification in nontarget cells 3.1. Inhibition of genotoxic effects (see 1 and 2) 3.2. Antioxidant activity and scavenging of free radicals 3.3. Antiinflammatory activity 3.3.1. Cyclooxygenase inhibition 3.3.2. Lipooxygenase inhibition 3.3.3. Inhibition of inducible nitric oxide synthase 3.3.4. Leukotriene receptor antagonism 3.4. Inhibition of proteases 3.5. Inhibition of cell proliferation 3.5.1. Inhibition of ornithine decarboxylase 3.5.2. Promoting proteasomal degradation of cyclins 3.5.3. Interference with multiple signaling pathways 3.6. Induction of cell differentiation 3.7. Modulation of cell apoptosis 3.8. Signal transduction modulation 3.9. Protection of intercellular communications SECONDARY PREVENTION 2. Inhibition of mutation and cancer initiation in target cells 2.1. Modification of transmembrane transport 2.1.1. Inhibition of cellular uptake 2.1.2. Stimulation of extrusion outside cells 2.2. Modulation of metabolism 2.2.1. Inhibition of activation of promutagens/ procarcinogens by Phase I enzymes 2.2.2. Induction of Phase I detoxification and Phase II conjugation pathways, or acceleration of decomposition of reactive metabolites 2.2.3. Stimulation of activation, coordinated with detoxification and blocking of reactive metabolites 2.3. Blocking or competition 2.3.1. Trapping of electrophiles by either chemical reaction or enzyme–catalyzed conjugation 2.3.2. Antioxidant activity and scavenging of reactive species 2.3.3. Protection of DNA nucleophilic sites 2.4. Inhibition of cell replication 2.5. Maintenance of DNA structure and modulation of DNA metabolism and repair 2.5.1. Increase of fidelity of DNA replication and repair of repair and/or reversion of DNA damage 2.5.3. Inhibition of error-prone repair pathways 2.5.4. Correction of hypomethylation 2.5.5. Inhibition of histone deacetylation 2.5.6. Blocking of telomerases or inhibition of their activity 2.6. Control of gene expression 2.6.1. Targeted inactivation of oncogenes 2.6.2. Inhibitionofoncogene expression 2.6.3. Inhibition of oncogene sequences or activity 2.6.3.1. Inhibition of translation targeted to oncogene mRNA 2.6.3.2. Inhibition of transcription of specific DNA sequences 2.6.3.3. Blocking of target genes 2.6.2.4. Farnesyltransferase inhibition 2.6.4. Neutralization or post–translational modification of oncogene products 2.6.5. Replacement of deleted tumor suppressor genes 2.6.6. Mimicking the DNA binding of tumor suppressor genes by antiidiotypic antibodies 2.6.7. Killing of cells lacking tumor suppressor genes S. De Flora and L.R. Ferguson, Mutat. Res., 591, 8–15, 2005 4. Inhibition of tumor progression 2.5.2. Stimulation 4.1. Inhibition of genotoxic effects (see 1 and 2) 4.2. Antioxidant activity and scavenging of free radicals 4.3. Inhibition of proteases 4.4. Signal transduction modulation 4.5. Effects on the hormonal status 4.5.1. Selective estrogen receptor modulation 4.5.2. Aromatase inhibition 4.5.3. Selective blocking of prostaglandin E2 receptors 4.5.4. Decrease in ovarian hormones by dietary isoflavones 4.5.5. Inhibiting the pituitary secretion of luteinizing hormone 4.5.6. Preventing conversion of testosterone into dehydrotestosterone by 5a–reductase 4.5.7. Selective androgen receptor antagonism 4.6. Effects on the immune system 4.7. Inhibition of angiogenesis 4.8. Antineoplastic activity by either mechanical, physical, chemical, or biological means TERTIARY PREVENTION 5. Inhibition of invasion and metastasis 5.1. Antioxidant activity and scavenging of free radicals 5.2. Signal transduction modulation 5.3. Inhibition of cell proliferation (see 3.4) 5.4. Modulation of cell apoptosis 5.5. Induction of cell differentiation 5.6. Inhibition of angiogenesis 5.7. Effect on cell-adhesion molecules 5.8. Inhibition of proteases involved in basement membrane degradation and modulation of the interaction with the extracellular matrix 5.9. Activation of antimetastasis genes PREVENTION OF LUNG TUMORS IN MICE NUMBER OF TUMORS/MOUSE 0.35 11.06 1.95 CONTROLS (STANDARD DIET) URETHANE (STANDARD DIET) URETHANE (DIET WITH NAC 0.2%) S. De Flora et al., Cancer Lett. 32, 235-241,1986 EXPRESSION OF 4858 GENES IN RAT LUNG A. Izzotti et al., Mutat. Res. 591, 212–223, 2005 SMOKE-FREE RATS SMOKE-EXPOSED RATS SAFETY SHAM NAC OPZ OPZ 5,6-BF + NAC PEITC I3C EFFICACY PEITC + I3C ECS OPZ NAC 5,6-BF OPZ + NAC I3C PEITC + I3C PEITC EFFECT OF ENVIRONMENTAL CIGARETTE SMOKE AND CHEMOPREVENTIVES ON miRNA EXPRESSION IN RAT LUNG 0 .6 PCA component 2 0 .5 ECS + PEITC + I3C 0 .4 ECS + OPZ + NAC 0 .3 ECS + PEITC 0 .2 ECS + NAC ECS + I3C ECS + OPZ 0 .1 ECS ECS + BF 0 NAC -0 .1 BF SHAM NAC + OPZ PEITC -0 .2 OPZ -0 .4 -0 .3 PEITC + I3C - 0 .2 - 0 .1 0 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 ANGIOGENESI E ANTIANGIOGENESI VASCOLARIZZAZIONE DI SPUGNE DI MATRIGEL NAC – NAC + T. Cai et al., Lab. Invest. 79, 1151-1159, 1999 CRESCITA DI SARCOMA DI KAPOSI UMANO IN TOPI NUDI CONTROLLI NAC 1.5 0.5 0 4.0 3.5 F E M M I N E M A S C H I M A S C H I 3.0 2.5 2.0 1.5 )3 Volume del tumore (cm 3 ) 1.0 F E M M I N E + + 1.0 0.5 0 5 10 15 20 25 30 5 10 15 20 25 30 Tempo (giorni) A. Albini et al., Cancer Res. 61, 8171-8178, 2001 THRESHOLDS IN CARCINOGENESIS? CARCINOGENESIS PROCESS TOXICOKINETIKS AND METABOLISM DNA DAMAGE AND REPAIR Exposure dose Pharmacologic dose Cellular dose Target dose Molecular dose INITIATION (days - weeks) MECCANISMI SOGLIE ? Apoptosis DNA repair PROMOTION (years - decades) BENIGN TUMOR PROGRESSION (~ 1 year) CANCER INVASION NEOPLASTIC MASS METASTASIS CARCINOGENICITY OF CHROMIUM IN HUMANS (IARC, Vol. 49, 1990) There is inadequate evidence for the carcinogenicity of metallic chromium and of Cr(III) compounds (Group 3) There is sufficient evidence for the carcinogenicity of Cr(VI) compounds (Group 1) as encountered in the chromate production, chromate pigment production and chromium plating industries o/e deaths ± 95% C.I. LUNG CANCER DEATHS IN CHROMATE PRODUCTION WORKERS 3.0 H.J. Gibb et al. Am. J. Ind. Med. 38: 115–126 (2000) 2.5 2.0 1.5 1.0 0.5 234 2,184 15,600 233,480 Exposure quartiles [ng Cr(VI)/m3–years] “For cancers other than those of the lungs and sinonasal cavity, no consistent pattern of cancer risk has been demonstrated in those workers exposed to chromium” International Agency for Research on Cancer (1990) Vol. 49 M.D. Cohen et al. (1993) Crit. Rev. Toxicol. 23: 255–281 R.B. Hayes (1997) Cancer Causes Control 8: 371–385 ATSDR, U.S. Dept. of Health and Human Services (2000) S. De Flora (2000) Carcinogenesis 21: 533-541 CARCINOGENICITY ASSAYS OF CHROMIUM COMPOUNDS IN RODENTS (IARC, 1990) Cr(VI) Cr(III) Other Cr compounds or mixtures Metallic Cr 3.6% 41.5% 58.5% 65 studies Positive Negative Uncertain 9.5% 90.5% 21 studies 100% 6 studies 10.7% 85.7% 28 studies CARCINOGENICITY OF Cr(VI) COMPOUNDS IN RODENTS Sodium chromate Chromic acid –+ Calcium chromate – +–– Zinc yellow Zinc chromates Barium chromate Lead chromates ––– – ++ –– – ––– ––– – intramuscolar intrafemural –– + ++– ++ Strontium chromate subcutaneous ––– – ––– intravenous + intraperitoneal intrabronchial + intrapleural intratracheal Sodium dichromate inhalation Compound oral Administration route +++ + + – – –– + +++ +++ +–– + + +++ –– +–– The results are those reviewed in Table 22 of IARC (1990), plus Snyder et al. (1997). +, significant increase of tumors in treated animals; –, no significant increase. Cr(VI) CARCINOGENICITY IN ANIMAL MODELS IS GOVERNED BY THRESHOLDS MECHANISMS Most results were negative (58.5%), due to complete Cr(VI) detoxification – Positive results (41.5%) were generated at one dose only, without any dose–response curve Cr(VI) induced tumors exclusively at implant sites, through administration routes that do not reproduce any human exposure and by–pass detoxification mechanisms MTD DOSE – + Cr(VI) mostly induced tumors in tissues having poor detoxification capacities The same Cr(VI) dose that was weakly carcinogenic, when massively given once per week, failed to induce tumors when subdivided into 5 weekly doses + – RESULTS OBTAINED WITH CHROMIUM COMPOUNDS IN CELLULAR SYSTEMS S. De Flora et al., Mutat. Res. 238, 99–172, 1990 700 data relative to 32 chromium compounds tested in 130 experimental test systems RESULTS OBTAINED WITH CHROMIUM COMPOUNDS IN CELLULAR SYSTEMS (S. De Flora et al., 1990) High solubility Medium solubility Low solubility 12.3% Cr(VI) 94.0% 6.0% 86.7% 13.3% 56.1% 31.6% 319 results 60 results 57 results 4.7% 11.8% Cr(III) 24.3% 71.0% 23.5% 64.7% 29.4% 52.9% 17.7% 169 results 17 results Positive Positive only following artificial solubilization Positive but contaminated with Cr(VI) Negative 17 results NUCLEUS CYTOPLASM (TARGET DOSE) EXTRACELLULAR (CELLULAR DOSE) mito c hon drio n Cr(V) ic as m l p o end m culu i t e r DNA (PHARMACOKINETIC DOSE) Cr(III) cytosol Cr 2– METABOLIC REDUCTION glutathione, cysteine, H 2O 2, ascorbate, riboflavin, cytochrome P-450, DT diaphorase, aldehyde oxidase L-Cr(III) anion channel protein CrO 4 REDUCTION IN BODY FLUIDS OR NONTARGET CELLS blood, digestive tract, lumen of terminal airw ays REACTIVE PRODUCTS ACTIVATION TRA NSC R Cr(VI) esters, Cr(V), Cr(IV), Cr(III), HO , RS , R DETOXIFICATION L 3+ Cr L IPT IO N mRNA TRA N SL AT ION enzyme substrate L L L product S. De Flora and K.E. Wetterhahn, Life Chem. Rep. 7, 169-244, 1989 L METABOLIC DEACTIVATION OF MUTAGENS S. De Flora, Nature 271, 455-456, 1978 METABOLIC DEACTIVATION OF MUTAGENS S. De Flora, Nature 271, 455-456, 1978 REDUCTION OF Cr(VI) BY HUMAN GASTRIC JUICE (S. De Flora et al., Mutat. Res. 192, 169–174, 1987) D I N N E BR R E LA U K N F C A pH im 0 5 0 4 0 3 0 2 0 1 0 0 0 T 6 4 2 H D o1 u28 e a y 2r0 I 22 24 4 6 8 1 I 10 12 I 14 16 T 8 Cr(VI) reduced (mg/ml/h) 6 H S REDUCTION OF Cr(VI) BY HUMAN ERYTHROCYTES (FL. Petrilli and S. De Flora 54,139–147, 1978) CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL POPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM SALIVA [0.7 – 2.1 mg Cr(VI)/day] LIVER CELLS [3,300 mg Cr(VI)] PORTAL SYSTEM BLOOD [187 - 234 mg Cr(VI)] GASTRIC JUICE [> 84 – 88 mg Cr(VI)/day] INTESTINAL BACTERIA [11 – 24 mg Cr(VI) eliminated daily with bacteria in feces] De Flora et al., Carcinogenesis 18, 531–537, 1997 LETHAL DOSE OF ORAL Cr(VI) IN HUMANS Amount of ingested compound (g) 100 10 1 0.1 K2Cr2O7 Na2Cr2O7 CrO3 0.01 Survived Died S. De Flora et al., Marcel Dekker, New York, 1995, pp. 716–725 ORAL CHROMIUM(VI) DOES NOT AFFECT THE FREQUENCY OF MICRONUCLEI S. De Flora, M. Iltcheva & R.M. Balansky, Mutat. Res. 610, 38–47, 2006 Adult BDF1 mice A single intraperitoneal injection of Cr(VI) (50 mg/kg b.w. = 1.2 g in a 70 kg man) increased the frequency of micronucleated PCE in bone marrow A single intragastric injection of Cr(VI) (50 mg/kg b.w. = 1.2 g in a 70 kg man) did not affect the frequency of micronucleated PCE in bone marrow Cr(VI), given daily with the drinking water for 210 consecutive days, up to 500 mg/l (10000 times the drinking water standard), did not affect the frequency of micronuclei either in bone marrow PCE or in peripheral blood NCE Pregnant Swiss albino mice and their fetuses Cr(VI), given daily with the drinking water during pregnancy, up to 10 mg/l (200 times the drinking water standard), did not affect the frequency of micronuclei in hematopoietic cells either of dams (bone marrow PCE) or of transplacentally exposed fetuses (liver and peripheral blood PCE) OCCUPATIONAL EXPOSURE TO Cr(VI) AND GASTROINTESTINAL CANCERS: A META-ANALYSIS N.M. Gatto et al., Cancer Epidemiol. 34, 388–399, 2010 ORAL ESOPHAGEAL STOMACH COLON RECTAL 17 studies Meta-SMR = 1.02 15 studies Meta-SMR = 1.17 29 studies Meta-SMR = 1.09 13 studies Meta-SMR = 0.89 20 studies Meta-SMR = 1.17 Cr(VI) REDUCTION BY HUMAN ALVEOLAR MACROPHAGES (PAM) (F.L. Petrilli et al., J. Clin. Invest. 77, 1917–24, 1986) Nonsmokers Exsmokers * Smokers * Recent smokers 0 1 2 3 4 5 6 Amount of Cr(VI) reduced (mg/106 PAM) * P < 0.01, as compared to nonsmok ers and exsmok ers 7 8 Cr(VI) REDUCTION BY HUMAN LUNG PARENCHYMA PREPARATIONS (S. De Flora et al., Cancer Res. 47, 4740–45, 1987) CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL POPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM BRONCHIAL TREE CELLS PERIPHERAL LUNG PARENCHYMA CELLS [260 mg Cr(VI)] ELF [0.9 – 1.8 mg Cr(VI)] PAM [136 mg Cr(VI)] BLOOD [187 – 234 mg Cr(VI)] De Flora et al., Carcinogenesis 18, 531–537, 1997 NUCLEUS CYTOPLASM (TARGET DOSE) EXTRACELLULAR (CELLULAR DOSE) mito c hon drio n Cr(V) ic as m l p o end m culu i t e r DNA (PHARMACOKINETIC DOSE) Cr(III) cytosol Cr 2– METABOLIC REDUCTION glutathione, cysteine, H 2O 2, ascorbate, riboflavin, cytochrome P-450, DT diaphorase, aldehyde oxidase L-Cr(III) anion channel protein CrO 4 REDUCTION IN BODY FLUIDS OR NONTARGET CELLS blood, digestive tract, lumen of terminal airw ays REACTIVE PRODUCTS ACTIVATION TRA NSC R Cr(VI) esters, Cr(V), Cr(IV), Cr(III), HO , RS , R DETOXIFICATION L 3+ Cr L IPT IO N mRNA TRA N SL AT ION enzyme substrate L L L product S. De Flora and K.E. Wetterhahn, Life Chem. Rep. 7, 169-244, 1989 L MAIN POSTGENOMIC ALTERATIONS INDUCED BY INTRATRACHEAL Cr(VI) IN RAT LUNG EXTRACELLULAR TRANSPORT MDR Cr(VI) REDUCTION DT diaphorase P450 reductases GSH peroxidase GSH S-transferase Aldehyde dehydrogenase EXTRACELLULAR TRANSPORT MDR Cr(VI) REDUCTION Percent Cr(VI) recovery 100 80 60 Cr(VI) + Microsomes Cr(VI) + NADPH 40 Cr(VI) + Microsomes + NADPH 20 0 DT diaphorase P450 reductases GSH peroxidase GSH S-transferase Aldehyde dehydrogenase 0 1 2 3 4 5 6 24 Incubation period (hours) From J.E. Gruber and K.W. Jennette, B.B.R.C. 82, 700, 1978 EXTRACELLULAR TRANSPORT MDR DECREASE OF Cr6+ MUTAGENICITY BY LUNG S12 FRACTIONS FROM RATS RECEIVING Cr6+ i.t.a 1200 without Cr(VI) REDUCTION DT diaphorase P450 reductases GSH peroxidase GSH S-transferase Aldehyde dehydrogenase Revertants per plate 1000 S12 1x1.25 mg/Kg/week ( weakly carcinogenic 800 b) 5x0.25 mg/Kg/week ( not carcinogenic b ) 600 400 200 TOXIC 0 0 10 20 30 40 50 Sodium dichromate (mg/plate) a Petrilli et al., Cancer Res. (1985) b Steinhoff et al., Exp. Pathol. (1986) MITOCHONDRIAL DAMAGE INDUCTION OF APOPTOSIS BY I.T. Cr(VI) EXTRACELLULAR TRANSPORT (F. D’Agostini et al., Carcinogenesis 23, 587–593, 2002) Ca++ 5 – fold increase MDR APOPTOSIS Bcl2DP Bcl2x short BclKP OXIDATIVE DAMAGE 22 – fold increase Superoxide dismutase Cr(VI) REDUCTION DT diaphorase P450 reductases GSH peroxidase GSH S-transferase Aldehyde dehydrogenase 1.2 – fold variation DNA DAMAGE DNaseI MITOCHONDRIAL DAMAGE DNA REPAIR Topoisomerase DNA polymerases AP endonuclease EXTRACELLULAR TRANSPORT CELL CYCLE Ca++ MAPKs JNKs CDKs Cyclins MDR APOPTOSIS Bcl2DP Bcl2x short BclKP PROTEIN DAMAGE OXIDATIVE DAMAGE Superoxide dismutase Cr(VI) REDUCTION DT diaphorase P450 reductases GSH peroxidase GSH S-transferase Aldehyde dehydrogenase Crystallins T complexes Heat shock p. Calnexin PROTEIN REPAIR/REMOVAL METABOLIC MECHANISMS AND Cr(VI) DETOXIFICATION The IARC Working Group (1990) “interpreted these findings as indicating mechanisms that limit the activity of Cr(VI) compounds in vivo ” The U.S. Environmental Protection Agency (1991) concluded that “the body’s normal physiology provides detoxification for Cr(VI)” The U.S. Department of Health and Human Services (2000) indicated that these “mechanisms limit the bioavailability and attenuate the potential effects of Cr(VI) compounds in vivo ” LE TECNOLOGIE 'OMICS S. De Flora & A. Izzotti, Mutat. Res., 667, 15–26, 2009 DNA RNA MicroRNA Proteine CONCLUSIONI GENOME Co lo r e d b SHAM y: v s CS, G e n e L is m t : m u ( 484) De f a u lt I n t e r p r e t a t io n ( sham . t xt ) MIRNOME TRANSCRIPTOME FATTORI PROTETTIVI PROTEOME Malattie cronicodegenerative e periodi critici della vita THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005 ITALY, GENERAL MORTALITY DATA, 1901–2000 35 ITALY, 2000 Population: 58 million Deaths: 1,276,000 Mortality rate: 22‰ Rates per 100.000 30 25 ITALY, 2000 Population: 58 million Deaths: 560,000 Mortality rate: 9.7‰ 20 15 10 5 ITALY, 1901 Population: 33 million Deaths: 726,000 Mortality rate: 22‰ 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 UNIVERSITA’ DI GENOVA DIPARTIMENTO DI SCIENZE DELLA SALUTE Laboratorio di Mutagenesi Ambientale e Prevenzione del Cancro Sebastiano La Maestra Giorgia Travaini Rosanna Micale Mariagrazia Longobardi Silvio De Flora Roumen Balansky Alberto Izzotti Tanya M. Pennisi Cristina Cartiglia Vinesh Kumar Thidil Pulyappadamba Carlo Bennicelli Ilaria Righi Maria Bagnasco Alessandra Pulliero Anna Camoirano Patrizia Larghero Francesco D’Agostini Alessandra Battistella
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