I have been privileged to witness and participate in the great growth of knowledge on chemical carcinogenesis and mutagenesis since 1939 when I entered graduate school in biochemistry at the University of Wisconsin­ Madison. I immediately started to work with the carcinogenic aminoazo dyes un­ der the direction of Professor CARL BAUMANN. In 1942 I joined a fellow graduate student, ELIZABETH CA VERT, in marriage and we soon commenced a joyous part­ nership in research on chemical carcinogenesis at the McArdle Laboratory for Cancer Research in the University of Wisconsin Medical School in Madison. This collaboration lasted 45 years. I am very grateful that this volume is dedi­ cated to the memory of Elizabeth. The important and varied topics that are reviewed here attest to the continued growth of the fields of chemical car­ cinogenesis and mutagenesis, including their recent and fruitful union with viral oncology. I feel very optimistic about the application of knowledge in these fields to the eventual solution of numerous problems, including the detection and estimation of the risks to humans of environmental chemical carcinogens and re­ lated factors.

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I. Relationships Between Mutagenesis and Carcinogenesis.- 1 Use of Mutations in Bacteria as Indicators of Carcinogenic Potential.- A. Introduction.- B. Historical Background.- C. Use of Assays.- I. General.- 1. Toxicology Screening.- 2. Research Uses.- II. Limitations.- 1. Metabolic Activation.- 2. Non-Genotoxic Carcinogens.- D. Methods.- I. General Introduction.- II. Outline Protocols for Reverse Mutation Assays.- 1. Plate-and-Treat Assays.- 2. Spot Tests and Gradient-Plate Assays.- 3. Treat-and-Plate Assays.- 4. Fluctuation Tests.- III. Forward Mutation Assays.- IV. Host-Mediated Assays.- E. Use of the Results from Mutation Assays.- I. Basic Meaning of Such Results.- II. Use of the Results.- 1. Extrapolation of the Results.- 2. Toxicological Significance of the Results.- F. Summary and Conclusions.- References.- 2 Mammalian Cell Mutations.- A. Introduction.- B. Genetics and Principles of Experimental Design.- I. Genetics.- II. Experimental Design.- C. Cell Types.- I. Assessment of Mutation in Rodent Cells.- 1. L5178Y Mouse Lymphoma Cells.- 2. Chinese Hamster V79 and CHO Cells.- 3. Mouse Lymphocytes.- II. Human Cells.- 1. Untransformed Fibroblasts.- 2. Transformed Fibroblasts.- 3. Lymphoblastoid Cell Lines.- 4. T Lymphocytes.- 5. Erythrocytes.- D. Use of Recombinant Shuttle Vectors.- I. Integrated Shuttle Vectors.- II. Extrachromosomal Shuttle Vectors.- E. Conclusions.- References.- 3 Mechanisms of Repair in Mammalian Cells.- A. Introduction.- B. Excision Repair.- I. Incision.- II. Excision and Repair Synthesis.- III. Enzymes Possibly Involved in Excision Repair.- IV. Ligation.- V. Heterogeneity of Damage and Repair.- VI. Preferential DNA Repair in Active Genes.- VII. Human Genes for Repair.- VIII. Repair of DNA and Strand Breaks.- C. Repair of Alkylated Bases.- D. Mechanisms of Tolerance.- I. DNA Synthesis on Damaged Templates.- II. Inducible DNA Processing.- E. Mismatch Repair.- F. Concluding Remarks.- References.- 4 Cancer-Prone Human Disorders with Defects in DNA Repair.- A. Introduction.- B. Xeroderma Pigmentosum.- I. Clinical Symptoms.- II. Cellular Sensitivities.- III. DNA Repair.- 1. Excision Repair.- 2. Correction of the Defect.- IV. XP Variants.- V. Mutagenesis.- VI. UV-Inducible Functions.- VII. Relationship to Clinical Symptoms.- C. Cockayne's Syndrome.- I. Clinical Symptoms.- II. Cellular and Molecular Studies.- III. Relationship to Clinical Symptoms.- D. Trichothiodystrophy.- E. Ataxia-Telangiectasia.- I. Clinical Symptoms.- II. Cellular Sensitivities.- III. DNA Repair.- IV. DNA Synthesis and the Cell Cycle.- V. Cytogenetics.- VI. Mutagenesis.- VII. Growth Properties.- 1. Growth Rate and Lifespan.- 2. Cellular Proteins.- VIII. Relationship to Clinical Symptoms.- F. Fanconi's Anaemia.- I. Clinical Symptoms.- II. Cellular Sensitivities.- III. Cytogenetics.- IV. DNA Synthesis and the Cell Cycle.- V. DNA Repair.- VI. Other Cellular Aspects.- VII. Mutagenesis.- G. Bloom's Syndrome.- H. Heterozygotes.- I. Future Prospects: Cloning the Genes.- References.- 5 DNA Repair and Carcinogenesis by Alkylating Agents.- A. Introduction.- B. Alkylating Carcinogens.- I. Classes of Compounds.- II. Spectrum of DNA Adducts.- III. Structure of Adducted DNA and Mutagenesis.- C. Factors Influencing Potency and Specificity of Alkylating Carcinogens.- D. Repair of Alkylated DNA in Mammalian Cells.- I DNA Repair In Vivo.- II. Properties of DNA Repair Proteins.- III. Distribution of Mammalian DNA Repair Activities.- E. Correlation of Adduct Persistence with Tumor Initiation.- I. Single-Dose Experiments.- II. Chronic Dose Experiments.- III. Role of Induction of DNA Repair Processes.- IV. Summary of In Vivo Adduct Persistence Experiments.- F. Cell-Specific DNA Repair.- G. Fine-Structure Specificity in DNA Repair.- I. Repair in Specific Genes and Regions of Chromatin.- II. Sequence Specificity of DNA Alkylation, Repair and Mutagenesis.- H. Correlation of Mutations in Oncogenes with DNA Damage and Repair.- I. Transfer and Expression of DNA Repair Genes.- J. Conclusions.- References.- II. Modifiers of Chemical Carcinogenesis.- 6 Tumour Promotion: Biology and Molecular Mechanisms.- A. Introduction.- B. Tumour Promotion in Mouse Skin.- I. Characteristics of Initiation and Promotion.- II. Models of Tumour Promotion.- 1. Clonal Expansion.- 2. Two-Stage Model for Promotion.- 3. Assessment of One- and Two-Stage Models.- III. Molecular Mechanism of Phorbol Ester-Induced Tumour Promotion.- 1. Specific Binding Sites Mediate Many Phorbol Ester Actions.- 2. Protein Kinase C is a Major Cellular Target for Phorbol Esters.- 3. Are All Phorbol Ester Effects Mediated via Protein Kinase C?.- 4. Do Non-Phorbol Ester Tumour Promoters Activate Protein Kinase C?.- C. Tumour Promotion in Liver.- I. Outline of Chemical Carcinogenesis.- II. Characteristics of Initiated Hepatocytes and Their Progeny.- III. Characteristics of Promotion by Phénobarbital.- IV. Alternative Regimes for Promotion.- V. Mechanism of Promotion by Phénobarbital and Related Xenobiotics.- 1. Mechanisms at the Cellular Level.- 2. Mechanisms at the Molecular Level.- D. Concluding Remarks.- References.- 7 Inhibition of Chemical Carcinogenesis.- A. Introduction.- B. Multistage Carcinogenesis in Mouse Skin.- C. Inhibitors of Tumor Initiation.- I. Antioxidants.- II. Flavones and Polyhydroxylated Compounds.- III. Halogenated Hydrocarbons and Other Enzyme Inducers.- IV. Weakly Carcinogenic or Noncarcinogenic Polycyclic Aromatic Hydrocarbons.- V. Miscellaneous Inhibitors of Tumor Initiation.- D. Inhibition of Tumor Promotion.- I. Antiinflammatory Steroids.- II. Retinoids.- III. Protease Inhibitors.- IV. Inhibitors of Arachidonic Acid Metabolism.- V. Antioxidants.- VI. Polyamine Synthesis Inhibitors.- VII. Miscellaneous Inhibitors of Tumor Promotion.- E. Conclusions.- References.- 8 Genetic Susceptibility to Chemical Carcinogens.- A. Introduction.- B. Genetic Susceptibility to Cancer in Experimental Animals.- I. Inbred Mouse Strains.- II. Interaction Between MHC Type and Chemical Carcinogens.- III. Genetic Interactions with Chemical Carcinogens in Animals.- 1. Lymphoma.- 2. Hepatoma.- 3. Lung.- 4. Mammary Gland.- 5. Other Tumours.- IV. Transplacental Carcinogenesis and Multigeneration Experiments.- C. Genetic Susceptibility to Cancer in Humans.- I. Association of Cancer with Normal Traits.- II. Cancer Families.- 1. Mendelian Inheritance.- 2. Familial Aggregation.- III. Evidence in Humans of Genetic Susceptibility to Chemical Carcinogens.- 1. Second Neoplasms.- 2. Migrant Studies.- 3. Susceptibility to Specific Carcinogenic Agents.- IV. Risk in Families of Patients with Chemically Induced Cancer.- D. Mechanisms of Genetic Susceptibility.- I. Genetic Factors in the Metabolism of the Carcinogen.- 1. Animal Evidence.- 2. Human Evidence of Genetic Control of Aryl …