Metabolic activation Additional mutationsProliferation Normal cell CARCINOGEN MALIGNANT NEOPLASM PRENEOPLASTIC CLONE Cell proliferation: Altered differentiation Permanent DNA lesion: Initiated cell Binding to DNA: Adduct formation Electrophilic intermediates Detoxification DetoxificationINITIATIONDNA repair Cell death PROMOTION Excretion
Fig. 6.32 Generalschemaofeventsinchemicalcarcinogenesis.Notethatpromoterscauseclonalexpansionoftheinitiatedcell,thusproducingapreneoplasticclone.Furtherproliferationinducedbythepromoterorotherfactorscausesaccumulationofadditionalmutationsandemergenceofamalignanttumor.
induction of cell proliferation is a sine qua non of tumor promotion. It seems most likely that while the application of an initiator may cause the mutational activation of an oncogene such as RAS, subsequent application of promoters leads to clonal expansion of initiated (mutated) cells. Forced to proliferate, the initiated clone of cells accumulates additional mutations, developing eventually into a malignant tumor. Indeed, the concept that sustained cell proliferation increases the risk for mutagenesis, and hence promotes neoplastic transformation, also is applicable to human carcinogenesis. For example, endometrial hyperplasia (Chapter 19) and increased regenerative activity that accompanies chronic liver cell injury are associated with the development of cancer in these organs. Were it not for the DNA repair mechanisms discussed earlier, the incidence of chemically induced cancers in all likelihood would be much higher. As mentioned previously, the rare hereditary disorders of DNA repair, including xeroderma pigmentosum, are associated with greatly increased risk for developing cancers induced by UV light and certain chemicals.
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ChemicalcarcinogenshavehighlyreactiveelectrophilegroupsthatdirectlydamageDNA,leadingtomutationsandeventuallycancer.
Direct-actingagentsdonotrequiremetabolicconversiontobecomecarcinogenic,whileindirect-actingagentsarenotactiveuntilconvertedtoanultimatecarcinogenbyendogenousmetabolicpathways.Hence,polymorphismsofendogenousenzymessuchascytochromeP-450mayinfluencecarcinogenesisbyalteringtheconversionofindirect-actingagentstoactivecarcinogens.
Afterexposureofacelltoamutagenoraninitiator,tumorigenesiscanbeenhancedbyexposuretopromoters,whichstimulateproliferationofthemutatedcells.
Examplesofhumancarcinogensaredirect-actingagents(e.g.,alkylatingagentsusedforchemotherapy),indirect-actingagents(e.g.,benzo(a)pyrene,azodyes,aflatoxin),andtumorpromoters.
Tumorpromotersactbystimulatingcellproliferation.Increasedproliferationmayoccurthroughdirecteffectsoftumorpromotersontargetcellsormaybesecondarytotissueinjuryandregenerativerepair.
Radiation, whatever its source (UV rays of sunlight, radiographs, nuclear fission, radionuclides), is an established carcinogen. Unprotected miners of radioactive elements have a 10-fold increased incidence of lung cancers. A follow-up study of survivors of the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia after an average latent period of about 7 years, as well as increased mortality rates for thyroid, breast, colon, and lung carcinomas. The nuclear power accident at Chernobyl in the former Soviet Union continues to exact its toll in the form of high cancer incidence in the surrounding areas. More recently, it is feared that radiation release from a nuclear power plant in Japan damaged by a massive earthquake and tsunami will result in significantly increased cancer incidence in the surrounding geographic areas.