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 Struct
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.
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