Progression The expression of malignant phenotype, the tendency to acquire more aggressive characteristics. metastasis Propensity for genomic instability and uncontrolled growth Further genetic changes: the activation of proto- oncogenes and the inactivation of tumor- suppressor genes
16 Progression • The expression of malignant phenotype, the tendency to acquire more aggressive characteristics, Metastasis • Propensity for genomic instability and uncontrolled growth • Further genetic changes: the activation of protooncogenes and the inactivation of tumorsuppressor genes
Activation of proto-oncogenes Point mutations: ras gene family, hotspots Overexpression amplification · Translocation Loss of function of tumor-suppressor genes usually a bimodal fashion Point mutation in one allele Loss of second allele by deletion, recombinational event, or chromosomal nondisjunction
17 • Activation of proto-oncogenes: – Point mutations: ras gene family, hotspots – Overexpression: • Amplification • Translocation • Loss of function of tumor-suppressor genes: usually a bimodal fashion – Point mutation in one allele – Loss of second allele by deletion, recombinational event, or chromosomal nondisjunction
Gene-environmental interactions The metabolism of xenobiotics by biologic systems Individualⅴ ariation The competition between activation and detoxication The alteration of genes by xenobiotics
18 Gene-environmental interactions • The metabolism of xenobiotics by biologic systems – Individual variation – The competition between activation and detoxication • The alteration of genes by xenobiotics
Classification of chemical carcinogens 1. Based on mechanisms (1)Genotoxic carcinogen(DNA-reactive) Direct-acting intrinsically reactive N-methyl-N-nitro-N-nitrosoguanidine( MNNG) methyl methanesulfonate(MMS) N-ethyl-N-nitrosourea(ENU), nitrogen and sulfur mustards Indirect-acting require metabolic activation by cellular enzyme to form the DNA-reactive metabolite(members of the cytochrome P450 family benzola]pyrene, 2-acetylaminofluorene, benzidine, Aflatoxin Bl, B2
19 Classification of chemical carcinogens 1. Based on mechanisms (1) Genotoxic carcinogen (DNA-reactive) • Direct-acting: intrinsically reactive N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS), N-ethyl-N-nitrosourea (ENU), nitrogen and sulfur mustards • Indirect-acting: require metabolic activation by cellular enzyme to form the DNA-reactive metabolite (members of the cytochrome P450 family) benzo[a]pyrene, 2-acetylaminofluorene, benzidine, Aflatoxin B1, B2
Chemical carcinogens Cytochrome and other P-450 in ER environmental pollutants Metabolism Binding of reactive intermediate to DNA Formation of excretable innocuous [ products Reactive intermediate Figure 1-39 Scheme for the metabolic activation of nonpolar polycylic chemicals by the cytochrome P-450 system in a typical mammalian cell to form reactive intermediates that bind to nucleophilic centers in DNA. ER, endoplasmic reticulum (Adapted from Nebert/294 with permission
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