ChemicalChemical--Induced Induced CarcinogenesisCarcinogenesisggCANCER:CANCER:““AAlti llti llti tlti tffdidiththhihiffhi hhi htilltillll““AAmulticausalmulticausal,,multistagemultistage groupgroup ofofdiseasesdiseasesthethemechanismsmechanismsofofwhichwhichareare stillstillonlyonlypartiallypartially knownknown””(IARC(IARC ScientificScientific Publications,Publications, 19921992))“Cancer“Cancerisisaagroupgroupofofdiseasesdiseasescharacterizedcharacterizedbybyuncontrolleduncontrolledgrowthgrowthandandspreadspreadofof“Cancer“Cancerisisaagroupgroupofofdiseasesdiseasescharacterizedcharacterizedbybyuncontrolleduncontrolledgrowthgrowthandandspreadspreadofofabnormalabnormal cellscells [[……]] thatthat cancan resultresult inin death”death” (American(American CancerCancer Society,Society, 20062006))Age-adjusted Cancer Death Rates, by Site, US, 1930-2005http://apps.nccd.cdc.gov/uscs/WHAT MAY CAUSE CANCER ?WHAT MAY CAUSE CANCER ?dddddd Hereditary disordersHereditary disorders ChemicalsChemicalsVirusesVirusesVirusesViruses Chronic inflammationChronic inflammation ??????liskintro.htmlvecare.com/ricersupportivp://www.cancFrom httpHistory of Chemical Carcinogenesisyg•Chemical carcinogenesis was first•Chemical carcinogenesis was first suggested by clinicians 200 years agoScrotal cancer in chimney sweepsPotts–Scrotal cancer in chimney sweeps -Potts– Nasal cancer and snuff dipping - HillTd 50 h i l i d–Today, >50 chemicals are recognized as human carcinogens• First experimental studies in animals d80were done ~80 years agoHistory of Chemical Carcinogenesis• Large numbers of chemicals were tested for i i i l i h 19701990carcinogenic potential in the 1970-1990s– Maximum Tolerated Doses (MTD) were used.–60% of rodent carcinogens were genotoxic– 40% of rodent carcinogens were nongenotoxic–Some chemicals were single site, single species carcinogensOth lti it lti i i–Others were multisite, multispecies carcinogens– Dose-response varies from <1/2 MTD to <1/1000 MTDli ih h il• Most regulations use straight mathematical extrapolation of high dose rodent data to predict risksrisksIARC (2010) - monographs.iarc.frCarcinogenic to humans (group 1)107 agents to date•Carcinogenic to humans (group 1) –107 agents to date•Probably carcinogenic to humans (group 2A) – 58•Possibly carcinogenic to humans (group 2B) – 249•Not classifiable as to its carcinogenicity to humans (group 3)512•Not classifiable as to its carcinogenicity to humans (group 3) –512•Probably not carcinogenic to humans (group 4) – 1U S EPA (2003)U.S. EPA (2003) •Carcinogenic to humans •Likely to be carcinogenic to humans •Suggestive evidence of carcinogenic potential•Suggestive evidence of carcinogenic potential •Inadequate information to assess carcinogenic potential •Not likely to be carcinogenic to humansU.S. NTP (2002)•Known to be a human carcinogen •Reasonably anticipated to be a human carcinogenCal/EPA (2004)Cal/EPA (2004) •Known to the state to cause cancerWORLD HEALTH ORGANIZATIONINTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC Monograph EvaluationsLYON, FRANCESlide courtesy of V. Cogliano (IARC)IARC:Slide courtesy of V. Cogliano (IARC)A tour of IARC’s classificationsPreamble, Part B, Section 6(d)Slide courtesy of V. Cogliano (IARC)Slide courtesy of V. Cogliano (IARC)www.epa.gov/irishttp://tools.niehs.nih.gov/srp/1/Resources/Arzuaga_IRIS_presentation.pdfCancer Cases Attributable to Environmental Carcinogens (Worldwide, 1990)Infections (viruses parasites H pylori)16%Infections (viruses, parasites, H. pylori)16%Tobacco (smoked and smokeless) 14%Occupation 4%Alcohol drinking 3%37%Diet and dietary components including contaminants 25%Pollution 2%Pollution 2%Reproductive factors 2%29%Chemical Carcinogenesis Chemical Carcinogenesis in the 21stCenturyNew perceptions of previously known carcinogens:Combined effects of multiple exposuresExamples:oAlcohol drinking and aflatoxinsoAlcohol drinking and aflatoxinso Alcohol drinking and HBV/HBCo Alcohol drinking and tobacco smokingo Tobacco smoking and asbestos/arsenic/radongStages of CarcinogenesisStages of CarcinogenesisInitiatingCell ProliferationInitiationInitiatingEventCell Proliferation(clonal expansion)PromotionCell ProliferationProgressionCell ProliferationMalignancyCellular and Molecular Mechanisms in Multistage Carcinogenesis: INITIATIONInitiating event involves cellular genome – MUTATIONSTt/tTarget genes: - oncogenes/tumor suppressor genes- signal transductionll l / t i l t-cell cycle/apoptosis regulatorsehind/“Simple”ov/sciencebeSimple genetic changester.cancer.gotp://newscentFrom httpSOURCES OF MUTATIONSSOURCES OF MUTATIONSSOURCES OF MUTATIONSSOURCES OF MUTATIONSENDOGENOUS DNA DAMAGEENDOGENOUS DNA DAMAGE EXOGENOUS DNA DAMAGEEXOGENOUS DNA DAMAGELifeLifeEnvironmentalEnvironmentalFreeFree PolymerasePolymeraseDepurinationDepurination StylesStylesAgentsAgentsRadicalsRadicals ErrorsErrorsDNA REPAIRDNA REPAIRCELL REPLICATIONCELL REPLICATIONMUTATIONMUTATIONChemical ExposureChemical Exposure(air, water, food, etc.)(air, water, food, etc.)pp()()Internal ExposureInternal ExposureMetabolic ActivationMetabolic ActivationMacromolecular BindingMacromolecular BindingDetoxicationDetoxicationDNADNARNARNAProteinProtein(Biomarker)(Biomarker)Biologically Effective DoseBiologically Effective DoseXXEfficiency of MispairingEfficiency of MispairingXXXXInitiationInitiationCell ProliferationCell ProliferationGENETIC AND EPIGENETIC MODELS OF THE CANCER INITIATIONEndoEndomentalmentalNormal cellsEndoEndomentalmentalNormal cellsogenousogenousEnvironmEnvironmALTERATIONS IN ogenousogenousEnvironmEnvironmACQUISITION OF ADDITIONAL Epigenetically ALTERATIONS IN CELLULAR EPIGENOMEClonal selection and ACQUISITION OF ADDITIONAL RANDOM MUTATIONSEpigenetically reprogrammed cellsClonal selection and expression of initiated cellsMutator phenotype cellsMutator phenotype cellsCancer cellsCancer cellsAccumulation of mutations during tumor progressionAccumulation of mutations during tumor progressionLoeb L.A. Cancer Res. 61:3230-9 (2001)Cellular and Molecular Mechanisms in Multistage Carcinogenesis: PROMOTIONReversible enhancement/repression of gene expression:-increased cell proliferationincreased cell proliferation- inhibition of apoptosisNo direct structural alteration in DNA by agent or its metabolitesNo direct structural alteration in DNA by agent or its
View Full Document
Unlocking...