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Chapter 8: Chemical Carcinogenesis

James E. Klaunig

  • Overview

  • Historical Background

    • Definitions

  • Multistage Carcinogenesis

    • Initiation

    • Promotion

    • Progression

  • Mechanisms of Action of Chemical Carcinogens

    • Genotoxic/DNA-Reactive Compounds

      • Direct-Acting (Activation-Independent) Carcinogens

      • Indirect-Acting Genotoxic Carcinogens

    • Mutagenesis

    • Damage by Alkylating Electrophiles

    • DNA Repair

    • DNA Repair Mechanisms

      • Mismatch Repair of Single-Base Mispairs

      • Excision Repair

      • End-Joining Repair of Nonhomologous DNA

    • Classes of Genotoxic Carcinogens

      • Polyaromatic Hydrocarbons

      • Alkylating Agents

      • Aromatic Amines and Amides

    • 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

      • Metals

    • 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

      • Chronic (Two Year) Bioassay

      • Organ-Specific Bioassays and Multistage Animal Models

    • Transgenic Animals in Carcinogenicity Assessment

      • New Approaches

  • Chemical Carcinogenesis in Humans

  • Classification Evaluation of Carcinogenicity in Humans

  • Summary

Overview

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.

Figure 8-1.

Proportions of human cancer deaths attributed to various factors. (Reproduced with permission from [no authors listed] Harvard reports on cancer prevention: causes of human cancer. Center for Cancer Prevention Harvard School of Public Health. Cancer Causes and Control. 1996;7 (Suppl 1):S3–S4, 1996.)

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Historical Background

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.

Table 8-1Historical Events in Chemically Induced Cancer
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Table 8-1 Historical Events in ...

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