Chemical Induction of Cancer : Modulation and Combination Effects an Inventory of the Many Factors which Influence Carcinogenesis

In the approach to the analysis of disease, including, of course, cancer, two major thrusts may be distinguished. These may be referred to, in shorthand, as agents and processes: the causative agents (chemical, microbial, physical, environmental, and psychosocial) and the organismic processes, initiated and furthered by the agents, culminating in observable pathology (at the macromolecular, cytological, histological, organ function, locomotor, and behavioral levels). The past 25 years, since the appearance of the first volume of the predecessor series (1) authored by the Editors of this present volume, have seen an impressive number of studies on chemicals (and other agents) as etiologic factors in the induction of cancer. The major emphasis has been on the discovery of many chemical carcinogens of widely different structures, their metabolism by various tissues and cells, and, in turn, their molecular-biochemical effects on the cells. This rapidly expanded body of information, as effectively covered in the predecessor volumes, is an excellent entree to the second half of the overall problem of chemical carcinogenesis, the processes. The active agents trigger a large array of molecular-biochemical alterations to which the target cells, target tissues, and target organisms respond in many select and common ways. This second major aspect of the induction of cancer by chemicals (and by other agents)- the sequence of cellular and tissue changes clearly relevant to cancer-remains the challenge for the future.

Prefatory Chapter Multifactor Interaction Network of Carcinogenesis― A “Tour Guide”.- I. Introduction. The Interaction Network as a Graph.- II. Review of Elements of the Network-An Analysis of Their Interrelationships.- A. Varieties of Initiation Processes.- B. Beyond Initiation.- C. Repositories of Inheritable Epigenetic Information.- D. Role and Control of Mixed-Function Oxidases.- E. Promoters versus Epigenetic Carcinogens.- F. Promoters, Inhibitors, Calorie Intake versus Rate of Cell Proliferation.- G. The Neuroendocrine Interface. Factors Affecting Hormonal Regulatory Pathways.- H. Factors Affecting the Systemic Immune Network. The Neuroimmunoendocrine Interface.- I. Central Role of the Effect of Aging.- J. Generation of Reactive Radical Species and Damage to Membranes.- K. Aging, Cancer, and Loss of Homeostatic Functions.- III. Closing Note.- References.- 1 Cross-Reactions between Carcinogens. Modification of Chemical Carcinogenesis by Noncarcinogenic Agents.- 2 Synergism and Antagonism between Chemical Carcinogens.- I. Introduction.- II. Sources and Selection of Data for Analysis.- III. Overview of Carcinogenic Effects of Selected Binary Combinations.- IV. Overview of Carcinogenic Effects of Selected Multiple (Nonbinary) Combinations of Structurally-Defined Chemical Compounds and Complex Mixtures.- V. Considerations on the Mechanisms Involved in the Synergistic and Antagonistic Interactions of Chemical Carcinogens.- References.- 3 Synergism in Carcinogenesis: Mathematical Approaches to Its Evaluation.- I. Theoretical Background.- A. Conditions for Substantiation of Synergism.- B. Classes of Synergism.- 1. Suggestion of Synergism.- 2. Apparent Synergism.- 3. Probable Synergism.- 4. Strict Synergism.- 5. Absolute Synergism.- C. Significance of Linearity of Dose-Response Curves.- D. Significance of Nonlinearity of Dose-Response Curves.- E. Multiplicative Synergism.- II. Examples of Substantiation of Classes of Synergism.- A. Suggestion of Synergism (Class 1 Synergism).- B. Apparent Synergism (Class 2 Synergism).- C. Probable Synergism (Class 3 Synergism).- D. Strict Synergism (Class 4 Synergism).- E. Absolute Synergism (Class 5 Synergism).- III. Discussion.- A. Definition and Statistical Considerations.- B. On Interaction between Initiation and Promotion in Epidemiological Data.- C. Some Principles of Testing for Synergism in Animals.- D. Comments on Experimental Design of Testing for Synergism.- E. Speculative Considerations on the Mechanism of Synergism.- Appendix I: Statistical Significance.- A. Significance of Linearity of Dose-Response Curves.- B. Significance of Nonlinearity of Dose-Response Curves; Substantiation of Strict Synergism.- C. If Tumor Incidence in the Control Group Is Unknown.- References.- 4 Inhibition of Chemical Carcinogenesis.- I. Introduction.- II. Experimental Systems.- III. Mechanisms of Inhibition.- A. Blocking Activities.- 1. Inhibition of Carcinogen Uptake.- 2. Inhibition of the Formation or Activation of Carcinogens.- 3. Deactivation of Carcinogens.- 4. Increase of Detoxification by Enzymatic Reaction.- 5. Prevention of Carcinogen Binding to DNA.- 6. Increase of the Level or Fidelity of DNA Repair.- B. Antioxidant Activities.- 1. Scavenging of Reactive Electrophiles.- 2. Scavenging of Oxygen Radicals.- 3. Inhibition of Arachidonic Acid (AA) Metabolism.- C. Antiproliferative/Antiprogression Activities.- 1. Modulation of Signal Transduction.- 2. Modulation of Hormonal/Growth Factor Activity.- 3. Inhibition of Oncogene Activity.- 4. Inhibition of Polyamine Metabolism.- 5. Induction of Terminal Differentiation.- 6. Restoration of Immune Response.- 7. Increasing Intercellular Communication.- 8. Restoration of Tumor-Suppressor Function.- 9. Induction of Programmed Cell Death (Apoptosis).- 10. Correction of DNA Methylation Imbalance.- 11. Inhibition of Angiogenesis.- 12. Inhibition of Basement Membrane Degradation.- 13. Activation of Antimetastasis Genes.- IV. Chemical Agents Classified by Structure or Biological Activity that Have Displayed Inhibition of Chemical Carcinogenesis.- A. Antihormones.- B. Anti-inflammatory Agents.- C. Antioxidants.- D. Arachidonic Acid (AA) Metabolism Inhibitors.- E. GSH Enhancers.- F. Ornithine Decarboxylase (ODC) Inhibitors.- G. Protein Kinase C (PKC) Inhibitors.- H. Retinoids/Carotenoids.- I. Thiols/Dithiolthiones/Sulfides.- J. Other Chemical Classes Associated with Inhibition of Carcinogenesis.- 1. Arylalkyl Isothiocyanates.- 2. Calcium Compounds.- 3. DHEA/DHEA Analogs.- 4. Disulfiram/Disulfiram Analogs.- 5. Glucarates.- 6. Indoles.- 7. Molybdenum Compounds.- 8. Monocyclic Terpenes/Isoprenylation Inhibiting Compounds.- 9. Protease Inhibitors.- 10. Selenium Compounds.- 11. Vitamin D3/Vitamin D3 Analogs.- V. Cancer Chemoprevention: The Applied Science of the Inhibition of Carcinogenesis.- References.- 5 Promotion and Cocarcinogenesis.- Section I Tumor Promotion in Skin.- I. Multistage Carcinogenesis in Skin: Historical Background and Basic Conceptual Developments.- A. From Coal Tar Painting to the Initiation-Promotion Experiment.- B. Initiation-Promotion in Mouse Skin: An Experimental Model.- C. Conversion and Promotion (“Two-Stage Tumor Promotion”).- II. Skin Tumor Promoters.- A. Tumor Promotion by Specific Interactions With Intracellular Signalling.- B. Tumor Promotion via Nonspecific Tissue Damage.- C. Skin Tumor Promoters Involved in the Etiology of Human Cancer.- III. The Response of the Skin to Tumor Promoters.- A. Tumor Development.- 1. Papillomas and Carcinomas.- 2. Species and Strain Differences.- 3. Tissue Specificity.- B. Morphological and Cytological Responses.- C. Biochemical Responses.- 1. Activation of Protein Kinase C.- 2. Effect on the Biosynthesis of Eicosanoids.- 3. Effect on the Generation of Reactive Oxygen Species.- 4. Induction of Ornithine Decarboxylase.- IV. The Biological Nature of Skin Tumor Promotion and Conversion.- A. Skin Tumor Promotion as the Consequence of a Chronic Regenerative Reaction.- B. Conversion and Wound Response.- V. Concluding Remarks.- References.- Section II Tumor Promotion in Liver.- I. Stages in Hepatocarcinogenesis.- II. Liver Tumor Promoters.- III. Specificity of Liver Tumor Promoters.- IV. Effectiveness of Promoter as Carcinogen Without Initiator; Effect of Reversion of the Initiation-Promotion Sequence.- V. Mechanisms of Tumor Promotion in Liver.- A. Role of Liver Growth, Cell Proliferation, and Cell Death.- B. Changes in Gap-Junction-Mediated Intercellular Communication.- C. Role of Reactive Oxygen Species.- VI. Quantitative Aspects of Tumor Promotion in Liver.- VII. Relevance of Liver Tumor Promoters to Humans.- References.- Section IIIA Note on Multistage Carcinogenesis in Other Organs and In Vitro.- References.- Section IIIB Note on Tumor Promoters, Cocarcinogens, and Nongenotoxic Carcinogens.- References.- 6 Computerized Data Management as a Tool to Study Combination Effects in Carcinogenesis.- I. Introduction.- II. Combination Effects Categories: Definitions.- III. Conceptual Principles Involved in the Development of ISS.- A. The “Inherent Cancer Hazard” Component.- B. The “Hazard Modification” Component.- IV. System Overview and Application to Sample Mixtures.- V. Closing Note.- Appendix A: List of Structural and Functional Classes of Chemicals in ISS.- Appendix B: Derivation of Class Hit Values (HB) as Inferences from Class Interactions.- 1. General Principles.- 2. The Class Pair Interaction Matrix.- 3. Absolute Cell Frequencies and Expected Cell Values.- 4. Representativeness of Classes in the Database.- 5. Calculation of HB Values.- 6. Preparing an Inferred HB Values Class Matrix; the Use of These Values in the Weighting Ratio.- References.- 7 Intercellular Communication: A Paradigm for the Interpretation of the Initiation/Promotion/Progression Model of Carcinogenesis.- I. Introduction: Cancer as a Problem of Homeostatic Dysfunction.- II. The Natural History of Carcinogenesis.- III. Intercellular Communication: a Process to Ensure Homeostasis.- IV. Dysfunctional Gap-Junctional Communication During Carcinogenesis.- V. Chemical Inhibition During Tumor Promotion.- VI. Oncogenes/Anti-Oncogenes or Tumor-Suppressor Genes and Intercellular Communication.- VII. Modulation of Gap-Junctional Intercellular Communication by Growth Factors.- VIII. Altered Gap Junction Function and “Partially Blocked Ontogeny” During Carcinogenesis.- IX. The Integration of Extracellular-Intracellular-Intercellular Communication Mechanisms for Maintaining Homeostasis.- X. Modulation of Gap-Junctional Communication and Its Implications for the Prevention and Treatment of Cancer.- References.- Appendix to Part 1 Chemical Cancerogenesis: Definitions of Frequently Used Terms.- I. Introduction.- II. Definitions.- A. Chemical Cancerogenesis.- B. Chemical Risk Factors of Cancer.- C. Solitary Cancerogens (Synonyms: Cancerogens, Complete Cancerogens).- D. Conditional Cancerogens (Conditionally Cancer-Generating Factors).- E. Multistage Model of Cancerogenesis (Initiation, Promotion).- F. Progression.- G. Cocancerogenesis.- H. Syncancerogenesis.- I. Anticancerogenesis.- J. Synpromotion.- K. Antipromotion.- L. Genotoxicity.- M. Threshold Values for Chemical Risk Factors of Cancer (Non-Observed Effect Level, No-Effect Level, Threshold Value).- 2 Exogenous Factors and Endogenous Biological Parameters That Modulate Chemical Carcinogenesis.- 8 Immunotoxicology of Chemical Carcinogens.- I. Introduction.- II. The Immune System.- A. T Cells.- B. B Cells.- C. Natural Killer Cells (NK Cells).- D. Monocytes and Antigen Processing.- E. Lymphocyte Activation.- 1. Role of the T Cell Receptor (TCR).- 2. Cytokines/Lymphokines/Monokines.- 3. Interleukins.- 4. B Cell Activation.- F. Regulation of Immune Response.- III. Immune Surveillance and Carcinogenesis.- IV. Immunotoxicology.- V. Chemical Carcinogens and Other Immunesuppressants: Effects on the Immune System.- A. Polycyclic Aromatic Hydrocarbons.- B. Asbestos.- C. Therapeutic Drugs.- D. “Immunotoxic” Polyclonal and Monoclonal Antibodies.- E. Halogenated Aromatic Hydrocarbons.- F. Pesticides.- G. Metals and Metalloids.- References.- 9 The Effect of Diet on Tumor Induction.- Section I. Effect of Caloric (Energy) Restriction.- I. Caloric Restriction Effects on Tumorigenesis: Historical Beginnings.- II. Modalities of Caloric Restriction.- III. The Early Work of Albert Tannenbaum.- IV. Caloric Restriction versus Dietary Fat Content.- V. Influence of the Timing of Caloric Restriction.- VI. Caloric Intake versus Caloric Expenditure.- VII. Mechanism of Action of Caloric Restriction.- VIII. Overnutrition-Related Factors and Lack of Muscular Activity versus Cancer Risk.- References.- Section II. Modulation by Protein and Individual Amino Acids.- I. Introduction.- II. Some Background Concepts.- A. Dietary Protein Requirement.- B. Tumor Protein Requirement.- III. Epidemiology.- A. Breast Cancer.- B. Colon Cancer.- C. Other Cancers.- IV. Animal Studies with Whole Proteins.- A. Mammary Tumors.- B. Colon Tumors.- C. Liver Tumors.- D. Pancreatic Tumors.- E. Kidney Tumors.- F. Pituitary Tumors.- G. Tumors in Other Organs.- V. Effect of Individual Dietary Amino Acids on Carcinogenesis.- A. Methionine.- B. Tryptophan.- C. Tyrosine and Phenylalanine.- D. Leucine and Isoleucine.- VI. Closing Note.- References.- Section III. Modulation by Vitamins.- I. Introduction.- II. Physiological and Biochemical Roles of Vitamins with Special Emphasis on Relationship to Carcinogenesis.- III. Vitamin Deficiency and Carcinogenesis.- A. Vitamin A Deficiency and Carcinogenesis.- B. Deficiency in B Vitamins and Related Compounds.- C. Vitamin C Deficiency and Carcinogenesis.- D. Vitamin D Deficiency and Carcinogenesis.- E. Vitamin E Deficiency and Carcinogenesis.- F. Lipotrope Deficiency and Carcinogenesis.- IV. Modulation of Carcinogenesis by Vitamin Supplementation.- A. Influence of Vitamin A on Chemical Carcinogenesis.- B. Influence of Vitamin B on Chemical Carcinogenesis.- C. Influence of Vitamin C on Chemical Carcinogenesis.- D. Influence of Vitamin D on Chemical Carcinogenesis.- E. Influence of Vitamin E on Chemical Carcinogenesis.- F. Influence of Other Vitamins, Lipotropes and Other Quasi-Vitamins on Chemical Carcinogenesis.- V. Closing Note.- References.- Section IV. Modulation by Minerals.- I. Introduction.- II. Selenium Modulation of Chemical Carcinogenesis.- A. Selenium Modulation of Colon Carcinogenesis.- B. Selenium Modulation of Liver Carcinogenesis.- C. Selenium Modulation of Mammary Gland Carcinogenesis.- D. Selenium Modulation of Carcinogenesis at Other Sites.- E. Modulation of Carcinogenesis by Selenium Restriction/Deficiency.- III. Copper Modulation of Chemical Carcinogenesis.- IV. Zinc Modulation of Chemical Carcinogenesis.- V. Modulation of Chemical Carcinogenesis by Other Minerals.- A. Magnesium.- B. Calcium.- C. Lead.- D. Iron.- E. Potassium.- F. Sodium.- G. Arsenic.- H. Iodine.- I. Germanium and Other Minerals.- References.- Section V. Dietary Fiber and Its Effect on Cancer Incidence.- I. Dietary Fibers: Sources, Classification, Definitions.- II. Methodological Concepts and Limitations of the Assessment of Fiber Effects.- III. Protection by Dietary Fiber Against Colorectal Cancer.- IV. Mechanism of Fiber Protection Against Colorectal Cancer.- V. Dietary Fiber Effect on Cancer of the Breast and Pancreas: Epidemiological Studies.- References.- Editors’ Note I to Chapter 9: Indirect Modification of Chemical Carcinogenesis by Nutritional Factors Through Regulation of the Mixed-Function Oxidase System.- References.- Editors’ Note II to Chapter 9: On Evidence for Preventive Significance of Dietary Supplementation.- References.- 10 The Effect of Animal Age on Tumor Induction.- I. Introduction.- II. Background.- A. The Aging Process.- B. Relationship Between Aging and Cancer.- C. Research Approaches.- III. Studies on Chemical Carcinogenesis in Aging Animals.- A. Polycyclic Aromatic Hydrocarbons.- 1. In Skin.- 2. In Cell Culture.- B. Aromatic Amines.- C. Nitrosamines Requiring Activation.- D. Direct-Acting Nitrosamines.- E. Halogenated Hydrocarbons.- IV. Studies on Chemical Carcinogenesis in Aging Humans.- V. Studies on Chemical Carcinogenesis During Other Phases of the Life Span.- VI. Host Factors Affecting Chemical Carcinogenesis in Aging.- A. Metabolism and Disposition of Carcinogens.- 1. Carcinogen Activation.- 2. Carcinogen Detoxification.- B. DNA Susceptibility to Chemical Damage.- C. DNA Repair.- D. Cell Proliferation.- E. Immune Competence.- VII. Closing Note.- References.- 11 The Effect of Hormones on Tumor Induction.- Section I. Brief Overview of the Endocrine System.- I. Mechanisms of Hormone Action: Interaction with Receptors.- A. Steroid Receptors: Structure and Function.- B. Amine and Peptide Hormone Receptors: Structure and Function.- II. Classification, Biosynthesis, Release, and Disposition of Hormones.- A. Classification of Hormones Based on Chemical Structure and Mechanism of Action.- B. Biosynthesis and Release of Hormones.- C. Patterns of Hormone Secretion.- D. Transport and Metabolism of Hormones.- III. Principal Component Segments of the Endocrine System.- A. The Hypothalamic-Pituitary Axis and Its Peripheral Gland Targets.- 1. Hypophysis.- 2. Adrenal Glands.- 3. Thyroid Gland.- 4. Gonads.- B. Hormonal Regulation of Calcium Homeostasis.- C. Hormonal Control of Energy Utilization and Storage.- IV. Feedback Control in the Endocrine System: A Synoptic Overview.- Reference Sources.- Section II. Hormonal Carcinogenesis.- I. Kidney.- II. Liver.- III. Prostate.- IV. Testes.- V. Mammary Gland.- VI. Uterus.- VII. Note on the Mechanisms of Hormonal Carcinogenesis.- References.- Section III. Effect of Hormones on Carcinogenesis by Nonhormone Chemical Agents.- I. Enhancement of Chemical Carcinogenesis by Hormones.- A. Mammary Gland.- B. Liver.- C. Ovary.- D. Epidermis.- E. Bladder.- F. Prostate.- G. Other Organ Sites.- II. Inhibition of Chemical Carcinogenesis by Hormones.- III. Some M...