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Overview
Historical Background
Multistage Carcinogenesis
Initiation
Promotion
Progression
Mechanisms of Action of Chemical Carcinogens
Genotoxic/DNA-Reactive Compounds
Mutagenesis
Damage by Alkylating Electrophiles
DNA Repair
DNA Repair Mechanisms
Classes of Genotoxic Carcinogens
Classes and Mode of Action of Nongenotoxic (Epigenetic) Carcinogens
Cytotoxicity
α2u-Globulin-Binding Drugs
Receptor-Mediated
Hormonal Mode of Action
DNA Methylation and Carcinogenesis
Oxidative Stress and Chemical Carcinogenesis
Oxidative DNA Damage and Carcinogenesis
Oxidative Stress and Cell Growth Regulation
Gap Junctional Intercellular Communication and Carcinogenesis
Inorganic Carcinogens
Modifiers of Chemical Carcinogenic Effects
Polymorphisms in Carcinogen Metabolism and DNA Repair
Proto-Oncogenes and Tumor-Suppressor Genes
Retroviruses
DNA Viruses
Proto-Oncogenes
Tumor-Suppressor Genes
Hormesis, Dose Response, and Carcinogenesis
Chemoprevention
Assessing Carcinogenicity of Chemicals
Short-Term Tests for Mutagenicity
In Vitro Gene Mutation Assays
In Vivo Gene Mutation Assays
Chromosomal Alterations
DNA Damage
Short-Term Tests: Transformation Assays
Chronic Testing for Carcinogenicity
Transgenic Animals in Carcinogenicity Assessment
Chemical Carcinogenesis in Humans
Classification Evaluation of Carcinogenicity in Humans
Summary
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Cancer is a disease characterized by mutation, modified gene expression, cell proliferation, and aberrant cell growth. It ranks as one of the leading causes of death in the world. In the United States, cancer ranks as the second leading cause of death, with over one million new cases of cancer diagnosed and more than 1.5 million Americans dying from cancer annually. Multiple causes of cancer have been established including infectious agents, radiation, and chemicals. Estimates suggest that 70% to 90% of all human cancers have a linkage to environmental, dietary, and behavioral factors (Fig. 8-1). Although our understanding of the biology of the progression from a normal cell to a malignant one has advanced considerably in the past several decades, many aspects of the cause, prevention, and treatment of human cancer in particular the influence of lifestyle remain unresolved.
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A strong historical foundation for the linkage of the induction of cancer by chemicals has been documented (Table 8-1). Several excellent reviews of the historical background of carcinogenesis and cancer research have been published (Creech, 2000; Diamandopoulos, 1996; Shimkin, 2008). Studies over the last three centuries on chemically induced cancer are marked initially by epidemiological observations followed by experimental studies involving animal carcinogenesis models.
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