Over the past two decades a number of attempts have been made, with varying degrees of success, to collect in a single treatise available information on the basic and applied pharmacology and biochemical mechanism of action of antineoplastic and immunosuppressive agents. The logarithmic growth of knowledge in this field has made it progressively more difficult to do justice to all aspects of this topic, and it is possible that the present handbook, more than four years in preparation, may be the last attempt to survey in a single volume the entire field of drugs employed in cancer chemotherapy and immunosuppression. Even in the present instance, it has proved necessary for practical reasons to publish the material in two parts, although the plan of the work constitutes, at least in the editors' view, a single integrated treatment of this research area. A number of factors have contributed to the continuous expansion of research in the areas of cancer chemotherapy and immunosuppression. Active compounds have been emerging at ever-increasing rates from experimental tumor screening systems maintained by a variety of private and governmental laboratories through­ out the world. At the molecular level, knowledge of the modes of action of established agents has continued to expand, and has permitted rational drug design to play a significantly greater role in a process which, in its early years, depended almost completely upon empirical and fortuitous observations.

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II Table of Contents.- Section C: Alkylating Agents.- 30 Chemistry of Alkylation.- Reaction Mechanism.- References.- 31 Molecular Biology of Alkylation: An Overview.- Alkylation of DNA.- Effects of Alkylating Agents on Bacteriophage.- Cellular Modification of Damaged DNA.- Functional Capacity of Alkylated Template.- References.- 32 Mechanism of Action of 2-Chloroethylamine Derivatives, Sulfur Mustards, Epoxides, and Aziridines.- The Mechanism of Alkylation.- Mechanism of Action at the Cellular Level.- A. Long Term Effects of the Alkylating Agents.- B. Antineoplastic Effects.- C. Effects on Hemopoietic Tissue.- D. Effects on Spermatogenesis.- E. Effects on the Immune Response.- Mechanism of Action at the Macromolecular Level.- A. Reactions with Enzymes and Coenzymes.- B. Reaction with Nucleic Acids.- Distribution and Metabolism of Alkylating Agents.- Conclusions.- References.- 33 Mechanism of Action of Methanesulfonates.- Whole Tissue Studies.- A. Antitumor Activity.- B. Spermatogenesis.- C. Hemopoietic Effects.- D. Immunosuppressive Properties.- E. Miscellaneous Effects.- Metabolism and Distribution Studies.- Cellular Studies.- Studies at the Molecular Level.- Mutagenic Action.- Conclusions.- References.- 34 Mechanism of Action of Mitomycins.- Molecular Mechanism of Action.- A. Interaction with DNA in Vitro.- B. Interaction with DNA in Intact Cells (DNA Damage and Repair).- C. DNA Synthesis and Degradation.- D. RNA Metabolism.- E. Synthesis of Enzymes.- Biological Effects of Mitomycins Related to Molecular Mechanism of Action.- A. Mutagenicity.- B. Chromosome Breakage.- C. Viruses, Phage, and Episomal DNA.- D. Mitosis.- E. Immunological Aspects.- References.- 35 Mechanism of Action of Nitrosoureas.- Chemistry.- Pharmacological Considerations.- Reactions with Biological Materials.- A. Alkylation.- B. Carbamoylation.- Biochemical Effects.- A. Synthesis of Macromolecules.- B. Enzyme Levels and Inactivation of Enzymes.- Biological Effects.- A. Effects upon Cell Cycle and Cytotoxicity during the Cycle.- B. Genetic Effects.- Conclusions.- References.- Section D: Hormones.- 36 Mechanism of Action of Glucocorticoids.- Biochemical Effects of Glucocorticoids on Lymphoid Tissues.- A. DNA Metabolism.- B. RNA and Protein Metabolism.- C. Carbohydrate Metabolism.- D. Changes in Enzyme Activity.- Glucocorticoid Receptors.- A. Studies in Animals.- B. Whole Cell Studies in Vitro.- C. Broken-Cell System.- Possible Mechanism of Action and Basis for Resistance to Glucocorticoids.- References.- 37 Mechanisms of Action of Estrogens.- Chemical Structure and Steroidogenesis.- Actions on Target Organs.- A. Accessory Sex Organs.- B. Pituitary and Hypothalamus.- C. Lipogenesis and Cholesterol.- D. Antiestrogens.- E. Breast and Breast Cancer.- F. Additional Effects of Estrogens.- Biochemical Basis of Action.- A. Specific Estrogen Binding Proteins.- B. Macromolecular Synthesis.- C. Carbohydrate Metabolism.- References.- 38 Mechanism of Action of Androgens.- Biosynthesis of Androgens.- Relative Potency of Androgens.- Actions on Target Organs.- A. Testis and Male Accessory Sex Organs.- B. Ovaries and Female Accessory Sex Organs.- C. Pituitary.- D. Breast and Breast Cancer.- E. Metabolic Actions.- F. Antiandrogens.- Mechanisms of Action.- A. Effects of Androgens on Synthesis of Macromolecules.- B. Androgen Receptor Macromolecules.- C. Energy Metabolism and Enzyme Changes.- References.- 39 Mechanism of Action of Progesterone.- Biologic Responses to Progesterone.- The Uptake and Metabolism of Progesterone.- Binding of Progesterone to Target Cells.- Sequence of Events in the Action of Progesterone.- References.- 40 Pharmacology and Clinical Utility of Hormones in Hormone Belated Neoplasms.- Hormone-Induced Tissue Growth and Neoplasia.- Antineoplastic Property of Steroid Hormones as Related to Their Biological Activities.- A. Estrogens and Antiandrogenic Effect.- B. Androgen and its Antiestrogenic Effect.- C. Antineoplastic Effect of Estrogen and Hypothalamic-Pituitary Regulation of Prolactin.- D. Effect of Progestogens on Endometrium, Mammary Gland, and Kidney, and Their Antitumor Activity.- E. Corticosteroids and Their Antitumor Activity.- F. Direct Effect of Steroid Hormones on Tumor Growth.- Metabolism of Steroids in Cancer.- A. Metabolism of Estrogens.- B. Metabolism of Androgens.- Clinical Use of Hormonal Steroids in the Treatment of Cancer.- A. Cancer of the Prostate.- I. Diethylstilbestrol (?,??-diethyl-4,4?-stilbenediol).- II. Chlorotrianisene (tri-p-anisylchloroethylene, TACE).- III. Corticosteroid Therapy.- B. Cancer of the Breast.- I. Androgen Therapy.- 1. Testosterone.- 2. Dihydrotestosterone (Stanolone, Androstanolone, Androstan-17 ?-ol-3-one).- 3. 17?-Methyltestosterone.- 4. Fluoxymestrone (9?-fluoro-11 ?-hydroxy-17?-methyltestosterone, Halotestin).- 5. 19-Nor-Testosterone.- 6. ?1-Testololactone (Teslac).- 7. Other Synthetic Androgens.- II. Estrogen Therapy.- III. Adrenocorticoid Therapy.- IV. Progesterone.- C. Endometrial Carcinoma.- D. Carcinoma of the Kidney.- E. Lymphomas and Leukemia.- Conclusions.- References.- Section E: Antimetabolites.- 41 Fluorinated Pyrimidines and Their Nucleosides.- Rationale.- Syntheses.- Physical, Chemical, and Conformational Properties.- Tumor-Inhibitory Properties.- Other Biological Effects.- A. Inhibition of the Growth of Cultured Cells.- B. Antiviral Activity.- C. Mutagenic Activity.- D. Teratogenic Activity.- E. Effects on Chromosomes.- F. Effects on Bacterial Cell Walls.- G. Antifungal Effects.- H. Immunosuppression.- Biochemical Summary.- A. Metabolic Degradation of the Pyrimidine Ring.- B. Anabolic Reactions along the Ribonucleotide Pathway.- C. Anabolic Reactions along the Deoxyribonucleotide Pathway.- D. Nucleoside Catabolic Reactions.- Inhibition of DNA Synthesis.- A. Cellular.- B. Enzymatic Mechanism.- Incorporation into DNA.- Effects on RNA Synthesis.- A. Mammalian.- B. Microorganisms.- C. Effects on Ribosome Biosynthesis.- Incorporation into RNA.- A. Total Cellular.- B. Viral RNA.- C. Transfer RNA.- D. Ribosomal RNA.- E. Messenger RNA.- Consequences of Incorporation into RNA.- A. Mutagenesis to RNA Viruses.- B. Effects on Protein Synthesis.- C. Effects on Enzyme Induction.- D. Coding Properties.- E. Translational Errors.- Pathways of Activation and Resistance.- A. Role of Catabolism.- B. Activation.- C. Resistance.- Effects on the Cell Cycle.- Preclinical Pharmacology.- Clinical Use.- Clinical Pharmacology.- References.- 42 Arabinosylcytosine.- Sy…