Antineoplastic and Immunosuppressive Agents

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.- Synthesis and Structure-Activity Relationships of the Arabinosides.- Assay Methods for Arabinosylcytosine.- Biological Actions.- A. Antitumor Effects in Experimental Systems.- B. Other Biological Effects.- Metabolic Fate of Arabinosylcytosine.- Biochemical Studies with Arabinosylcytosine.- A. Uptake and Phosphorylation of Ara-C.- B. Inhibition of DNA Biosynthesis.- C. Ribonucleoside Diphosphate Reductase.- D. DNA Polymerase.- E. Incorporation of Ara-C into Nucleic Acids.- F. Miscellaneous Biochemical Effects.- G. Resistance to Arabinosylcytosine.- Conclusions.- References.- 43 Clinical Pharmacology of Arabinosylcytosine.- Effect of Route of Administration.- A. Intravenous Administration - Single Dose.- I. Volume of Distribution.- II. Half-Life.- III. Metabolism.- 1. Plasma.- 2. Leukemic Cells.- IV. Excretion.- B. Oral Administration.- I. Absorption.- II. Effect of l-(?-d-ribofuranosyl)-4-hydroxy-3,4,5,6-tetrahydropyrimidine-2-(lH)one (Tetrahydrouridine, THU).- C. Intrathecal Administration.- D. Intramuscular and Subcutaneous Administration.- Toxicity.- A. Myelosuppression.- B. Megaloblastosis and Unbalanced Growth.- C. Chromosomal Aberrations and Teratogenesis.- D. Other Toxic Effects.- Effect of Schedule, Dose, and Strategy of Treatment.- A. Effect of Duration of Continuous Infusion on Clinical Toxicity.- B. Effect of Dose and Schedule on Pharmacological Findings.- I. Dose.- II. Schedule.- C. Clinical Results for Acute Leukemia and the Relationship of Schedule to Effectiveness.- Combination Chemotherapy.- A. Ara-C and Cyclophosphamide.- B. Ara-C and 1,3-bis(2-Chloroethyl) -1 -Nitrosourea (BCNU).- C. Ara-C and 6-Thioguanine (TG).- D. Ara-C and Methyl Mitomycin (Porfiromycin).- Resistance to Ara-C as Related to Kinase: Deaminase Ratios and to Intracellular Ribonucleotide Concentrations.- Perspectives.- A. Tetrahydrouridine (THU).- B. l-?-D-Arabinofuranosylcytosine 5?-Adamantoate (AdO-Ara-C).- C. Other Ara-C Analogs.- I. 2,2?-0-Cyclocytidine (Cyclocytidine).- II. Arabinosylcytosine 3-N-0xide (Ara-C-3-N-Oxide).- D. Sparing Action by Uridine.- References.- 44 Halogenated Pyrimidine Deoxyribonucleosides.- Chemistry.- A. Synthesis.- I. Synthesis of Nucleosides Halogenated in the Pyrimidine Moiety.- II. Synthesis of Radioactive Halogenated Nucleosides and Nucleotides.- III. Synthesis of Nucleosides Halogenated in the Sugar Moiety.- IV. Synthesis of Nucleotides Halogenated in the Pyrimidine Moiety.- V. Synthesis of Halogenated Nucleic Acid.- B. Stability of Nucleosides.- C. Steric Effects.- D. Ionization Effects.- E. Molecular Conformation.- Metabolism.- A. Anabolism.- B. Catabolism.- C. Enzyme Inhibition.- D. Augmentation of Utilization of Halogenated Deoxyribonucleosides.- I. Inhibition of Thymidylate Synthetase.- II. Inhibition of Nucleoside Phosphorylase.- III. Inhibition of Pyrimidine Degradation.- IV. Complex Formation.- V. Alteration of Structure.- VI. Improved Regimens.- Physical Effects of Incorporation of Halogenated Uracil Derivatives into DNA.- A. Increased Lability to Stress.- B. Increased Density.- C. Increased Temperature (Tm) for DNA Denaturation.- D. Decreased pH for DNA Denaturation.- E. Increased Sensitivity to Heat Degradation.- Biological Consequences of Incorporation of Halogenated Uracil Derivatives into DNA.- A. Mutagenic Effects.- B. Inhibition of Cellular Division.- I. Cell Culture.- II. Animals.- C. Inhibition of Viral Replication.- D. Effect on Oncogenic Viruses.- E. Effects on Transformation, Conjugation, and Transduction.- F. Inhibition of Antibody Production.- G. Effects on Embryonic Development and Differentiation.- H. Toxicity.- Marker Function.- Radiosensitization.- Clinical Use.- Mode of Inhibition.- Conclusions.- References.- 45 Azapyrimidine Nucleosides.- Review of Existing Azapyrimidine Nucleosides.- A. 6-Azapyrimidine Nucleosides.- B. 5-Azapyrimidine Nucleosides.- C. 6-Azauridine.- I. Molecular Mechanism of Inhibitory Effects.- II. Biological Effects.- 1. Virostatic Activity.- 2. Antineoplastic Effects.- 3. Immunosuppressive Activity.- 4. Cholesterol and Lipid Changes Induced by 6-Azauridine.- 5. Embryotoxic Effects.- III. Pharmacological Studies.- IV. Clinical Application.- 1. Virostatic Effects.- 2. Antineoplastic and Antihyperplastic Effects.- 3. Effect on Psoriasis.- D. 5-Azacytidine.- I. Molecular Mechanism of Inhibitory Action.- II. Biological Effects in Animal Systems.- III. Clinical Studies.- References.- 46 Showdomycin, 5-Hydroxyuridine, and 5-Aminouridine.- Chemistry of Showdomycin.- Metabolism of Showdomycin.- Inhibitory Effects of Showdomycin.- Chemistry and Metabolism of 5-Hydroxyuridine.- Inhibitory Effects of 5-Hydroxyuridine.- Chemistry, Metabolism, and Inhibitory Effects of 5-Aminouridine.- References.- 47 6-Thiopurines.- Metabolism of 6-Mercaptopurine and 6-Methylthioinosine.- A. Anabolism.- I. 6-Thioinosinate.- II. 6-Methylthioinosinate.- III. 6-Thioxanthylate.- IV. Other Anabolites of 6-Mercaptopurine.- V. 6-Thioinosine.- B. Catabolism.- Metabolism of 6-Thioguanine.- A. Anabolism.- I. 6-Thioguanosine Phosphates.- II. Deoxythioguanosine Phosphates.- III. Other Anabolites of 6-Thioguanine.- IV. 6-Thioguanosine and ?-2?-Deoxythioguanosine.- B. Catabolism.- Metabolic Effects of 6-Mercaptopurine and 6-Methylthioinosine.- A. The Free Base, 6-Mercaptopurine.- B. Nucleotide Anabolites.- I. Inhibition of Purine Ribonucleotide Synthesis de novo.- II. Inhibition of Purine Ribonucleotide Interconversions.- III. Incorporation into DNA.- IV. Resistance to 6-Mercaptopurine.- V. Conclusions.- Metabolic Effects of 6-Thioguanine.- A. The Free Base, 6-Thioguanine.- B. Nucleotide Anabolites.- I. Inhibition of Purine Ribonucleotide Synthesis de novo.- II. Inhibition of Purine Ribonucleotide Interconversions.- III. Incorporation into DNA.- IV. Delayed Cytotoxicity.- V. Conclusions.- Combination Chemotherapy.- References.- 48 Azathioprine.- (Basic Aspects).- Biochemical Effects.- Biological Effects.- A. Classes of Lymphocytes and Their Interactions.- B. Effects on Cells in Vitro.- C. Effects on the Immune Response.- I. Antibody Formation.- II. Cell-Borne Immunity.- D. Antitumor Effects.- I. In Rodents.- II. In Man.- E. Comparison of 6-Mercaptopurine and Azathioprine.- Clinical Pharmacology.- A. Toxicity.- B. Tissue Distribution.- C. Metabolism of Azathioprine.- I. Introduction.- II. Urinary Metabolites.- 1. 35S-Azathioprine.- 2. 14C-Azathioprine.- III. Blood Levels.- 1. 35S-Azathioprine.- 2. 14C-Azathioprine.- 3. Rosette Inhibitory Activity (RIA).- IV. Effect of Disease Conditions.- 1. Renal Insufficiency.- 2. Gout.- 3. Lesch-Nyhan Syndrome.- 4. Liver Disease.- D. Teratology.- I. Chromosome Studies.- II. Teratogenesis in Laboratory Animals.- III. Clinical Experience.- E. Effects on Immunological Status.- I. Tests for Immunological Reactivity.- II. Infections.- III. Carcinogenesis.- Conclusions.- References.- 49 Purine Arabinosides, Xylosides, and Lyxosides.- 9-?-D-Arabinofuranosyladenine (Ara-A).- 9-?-D-Arabinofuranosylguanine (Ara-G).- 9-?-d-Arabinofuranosylhypoxanthine (Ara-H).- 9-?-D-Arabinofuranosyl-6-Mercaptopurine (Ara-6-MP).- 9-?-D-Arabinofuranosyl-6-Thioguanine (Ara-TG).- 9-?-D-Xylofuranosyladenine (Xyl-A).- 9-?-D -Xylofuranosyl-6-Mercaptopurine (Xyl-6-MP).- 9-?-D-XyIofuranosyl-6-Thioguanine (Xyl-TG).- 9-?-D-Lyxofuranosyladenine (Lys-A).- 9-?-D-Lyxofuranosyl-6-Mercaptopurine (Lyx-6-MP).- References.- 50 Antibiotics Resembling Adenosine: Tubereidin, Toyocamycin, Sangivamycin, Formycin, Psicofuranine, and Decoyinine.- Pyrrolopyrimidine Nucleosides: Tubereidin, Toyocamycin, and Sangivamycin.- A. Common Pathway of Biosynthesis.- B. Tubereidin: An Anabolic Analog of Adenosine.- C. Biochemical Basis for the Cytotoxicity of Tubereidin.- I. Feedback Inhibition of Purine Nucleotide Biosynthesis by Tubercidin Mono-phosphate.- II. Impairment of Some Vital Function of ATP.- III. Formation of an Analog of Cyclic AMP.- IV. Impairment of Some Reaction Depending on NAD Cofactors.- V. Formation of Fraudulent Macromolecules that can Impede Protein or Nucleic Acid Synthesis.- VI. Different Action of Tubercidin in Cells of Different Origin.- D. Comparison of Toyocamycin and Sangivamycin with Tubercidin.- E. Potential for Chemotherapy.- Formycin.- A. Enzymatic Studies.- B. Biopolymers Containing Formycin.- C. Potential for Chemotherapy.- Inosine Analogs: Formycin B and 7-Deazainosine.- A. Formycin B.- B. 7-Deazainosine.- Psicofuranine, Decoyinine, and Mycophenolic Acid.- A. Rediscovered Antibiotics.- B. Biochemical Sites of Action.- I. Psicofuranine.- II. Decoyinine.- III. Mycophenolic Acid (MPA).- C. Potential for Chemotherapy.- Concluding Comments.- References.- 51 8-Azaguanine.- Early Investigations.- Pharmacological Behavior.- Effect of 8-Azaguanine and Its Derivatives on Enzymes.- A. Degradative Enzymes.- B. Anabolic Enzymes.- C. Metabolic Enzymes.- D. RNA Polymerase, DNA Polymerase, and Ribonuclease (RNAase).- Effects of 8-Azaguanine on Protein Synthesis.- Incorporation of 8-Azaguanine into Nucleic Acids.- References.- 52 Folate Antagonists.- Basic Considerations.- A. Structure and Mechanism of Action of Folate Antagonists.- B. Mechanism of Cell Death.- Pharmacology of Folate Antagonists.- A. Absorption.- B. Transport.- C. Distribution of Folate Antagonists.- D. Metabolism.- E. Excretion.- F. Mechanisms of Drug Resistance.- Clinical Application.- A. General Considerations.- B. Toxic Effects.- C. Treatment of Neoplastic Disease: General Principles.- D. Treatment of Specific Tumors.- I. Choriocarcinoma.- II. Acute Leukemia.- III. Head and Neck Cancer.- IV. Breast Cancer.- V. Lung Cancer.- VI. Lymphoma.- VII. Brain Tumors.- VIII. Primary or Metastatic Liver Tumors.- IX. Mycosis Fungoides.- X. Miscellaneous Solid Tumors.- XI. Nonneoplastic Diseases.- References.- 53 Glutamine Antagonists.- Metabolic Effects of Glutamine Analogs.- A. Azaserine and DON.- I. Isolation and General Biological Activity.- II. Inhibition of Purine Biosynthesis.- III. Inhibition of Pyrimidine Biosynthesis.- IV. Inhibition of Synthesis of NAD.- V. Inhibition of Synthesis of Glucosamine.- VI. Inhibition of Synthesis of Asparagine.- VII. Inhibition of Synthesis of Anthranilic Acid and p-Aminobenzoic Acid.- VIII. Synthesis of Histidine.- IX. Effects on Glutaminase and Glutamine Synthetase.- X. Other Actions.- XI. Mechanism of Growth Inhibition by Azaserine and DON.- B. Conjugates of DON.- C. Amide Derivatives of Glutamine: ?-Glutamylhydrazide and ?-N-Benzylglutamine.- D. O-Carbamyl-l-Serine and O-Carbazyl-l-Serine.- E. S-Carbamyl-l-Cysteine.- F. Albizziin.- Agents Affecting Synthesis and Degradation of Glutamine.- A. Inhibitors of Glutamine Synthetase.- B. Glutaminase.- Glutamine Analogs as Antitumor Agents.- Glutamine Analogs as Immunosuppressive Agents.- References.- 54 Cytotoxic Amino Acid Analogs.- Amino Acid Analogs and Anticancer Properties.- A. Aspartic Acid and Asparagine.- B. Basic Amino Acids.- I. Arginine.- II. Histidine.- III. Lysine.- C. Aromatic Amino Acids.- I. Phenylalanine.- II. Tyrosine.- III. Tryptophan.- D. Sulfur-Containing Amino Acids.- I. Methionine.- II. Cysteine and Cystine.- E. Leucine, Isoleucine, Valine, and Other Amino Acids.- I. Leucine, Isoleucine, and Valine.- II. Other Amino Acids.- Amino Acid Analogs and Immunosuppression.- Future Considerations.- References.- 55 Cytotoxic Analogs of Pyridine Nucleotide Coenzymes.- Analogs of NAD.- References.- 56 Triazenoimidazoie Derivatives.- Chemistry.- 5-(3,3-Dimethyl-1 -Triazene) Imidazole-4-Carboxamide (DIC, NSC-45388).- 5-[3,3-bis(2-Chloroethyl)-l-Triazeno]Imidazole-4-Carboxamide (BIC, NSC-82196).- Structure-Activity Relationships.- References.- Section F: Additional Cytotoxic Agents.- 57 Cytotoxic Inhibitors of Protein Synthesis.- Classification of Inhibitors.- Effects on Protein Synthesis and Polyribosome Structure.- Inhibitors.- A. Harringtonine.- I. General.- II. Mechanism of Action.- III. Other Cephalotaxus Alkaloids.- B. Pactamycin.- I. General.- II. Mechanism of Action.- C. Emetine.- I. General.- II. Mechanism of Action.- III. Structure-Activity Relationships.- IV. Effects on Synthesis of RNA.- V. Mechanism of Cytotoxicity.- D. Cycloheximide.- I. General.- II. Mechanism of Action.- III. Structure-Activity Relationships.- IV. Topological Similarity to the Ipecac Alkaloids.- V. Effects on Synthesis of RNA.- E. Tylocrebrine.- I. General.- II. Mechanism of Action.- F. Anisomycin.- I. General.- II. Mechanism of Action.- III. Structure-Activity Relationships.- G. Sparsomycin.- I. General.- II. Mechanism of Action.- H. Paederin.- I. General.- II. Mechanism of Action.- References.- 58 Selective Interruption of RNA Metabolism by Chemotherapeutic Agents.- Nucleolus.- Nuclear Heterogeneous RNA (HnRNA) and Messenger RNA (mRNA).- 4S and 5S RNA.- Mitochondrial RNA.- Some Examples of the Use of Selective Inhibitors.- References.- 59 Actinomycin.- Site of Action in Mammalian Cells.- Structural Features Required for Biological Activity.- Models of Actinomycin Binding Site on DNA.- Clinical Uses of Actinomycin D.- Carcinogenicity of Actinomycin D.- References.- 60 Dannomycin (Daunorubiein) and Adriamycin.- Chemistry.- Activity on Normal and Neoplastic Cells in Vitro.- Activity on Experimental Tumors.- Biochemical Effects and Mechanisms of Action.- Resistance to Daunomycin.- Antiviral Activity.- Pharmacological and Toxicological Studies.- References.- 61 Chromomycin, Olivomycin, and Mithramycin.- Chemistry and Mechanism of Action.- Antitumor Activity.- Pharmacology.- Clinical Investigations.- References.- 62 Nogalamyein.- Chemistry of Nogalamyein.- In Vitro Studies.- A. Antibacterial Activity.- B. Cytotoxicity to Mammalian Cells.- C. Characteristics of Nogalamyein - DNA Interaction.- D. Effects of Nogalamyein on RNA Synthesis.- E. Other Activities Inhibited by Nogalamyein.- F. Phase Specificity of Nogalamyein.- G. Comparative Biological Activity of Nogalamyein and Its Derivatives.- In Vivo Studies.- A. Enzyme Synthesis in Regenerating Liver.- B. Whole Animal Toxicity.- C. Antitumor Activity.- References.- 63 Streptonigrin.- Biological Properties.- Biochemical Effects.- Clinical Studies.- Derivatives of Streptonigrin.- References.- 64 Anthramycin.- Cytotoxic, Antimicrobial, and Chemosterilant Properties.- Effects on Macromolecular Synthesis in Cultured Cells.- Interaction of Anthramycin with DNA.- Structure-Activity Relationships.- Conclusions.- References.- 65 Camptothecin.- Pharmacokinetics.- Antitumor Properties.- Effects on Cultured Cells.- Effects on Mammalian Viruses.- Structure-Activity Relationships.- Mechanism of Action.- Conclusions.- References.- 66 3?-Deoxyadenosine and Other Polynucleotide Chain Terminators.- Enzymatic Studies.- A. Deamination.- B. Phosphorylation.- Effects of Phosphorylated Derivatives.- Effects on Whole Cells.- A. Growth.- I. 3?-Deoxyadenosine and 3'-Amino-3'-Deoxyadenosine.- II. 3?-Deoxyinosine and 3'-Deoxyadenosine N1-Oxide.- III. Other 3?-Deoxyribonucleosides.- IV. 3?-Amino Substituted Compounds.- V. 3?-Halogen Substituted Compounds.- VI. 2?,3'-Dideoxyribonucleosides.- B. Mitosis and Chromosomes.- C. Uptake and Metabolism.- RNA Synthesis.- A. Ehrlich Ascites Cells.- B. HeLa Cells.- C. H.Ep. Cells.- References.- 67 Yinea Alkaloids and Colchicine.- Basic Considerations.- A. Chemical Nature and Structure-Activity Relationships.- I. Vinca Alkaloids.- II. Colchicine Derivatives.- III. Podophyllotoxin and Griseofulvin.- B. Biological Activity.- I. Mitotic Arrest.- II. Antitumor Effects.- III. Anti-Inflammatory Action.- VI. Other Biological Effects.- C. Microtubule Interaction.- D. Biochemical Effects.- I. Nucleic Acid Biosynthesis.- II. Protein Biosynthesis.- III. Lipid Metabolism.- IV. Miscellaneous Biochemical Effects.- E. Metabolism and Distribution.- Clinical Considerations.- A. Drugs, Dosage, and Administration.- B. Toxicity.- The Place of the Vinca Alkaloids in the Chemotherapy of Cancer.- References.- 68 L-Asparaginase: Basic Aspects.- Assay of Enzyme Activity.- Distribution and Antitumor Activity.- Isolation and Purification.- Properties and Structure.- A. D-Asparagine.- B. Glutamine.- C. 5-Diazo-4-Oxo-L-Norvaline (DONV).- D. l-?-Cyanoalanine.- E. ?-Aspartylhydroxamate.- F. ?-Methyl-L-Aspartate.- G. Macromolecules.- Pharmacological Effects.- Immunological Studies.- Biochemical Studies.- Toxicological Effects.- Asparagine Synthetase.- References.- 69 L-Asparaginase: Current Status of Clinieal Evaluation.- Properties of the Enzyme Preparation.- Distribution and Elimination.- Dose and Route of Administration.- Effects of Asparaginase Therapy on Plasma Amino Acid Levels.- Therapeutic Effects.- A. Spectrum of Response.- B. Relation of Incidence and Duration of Remissions to Dose and Schedule of Administration of Asparaginase.- C. Central Nervous System Leukemia.- D. Combination Therapy.- E. Resistance.- Toxic Effects.- Conclusions.- References.- 70 Procarbazine.- Tumor Inhibition.- Chemical Properties.- Pharmacology.- Metabolism.- Mode of Action of Procarbazine.- Clinical Aspects.- References.- 71 Bis-Guanylhydrazones.- Methylglyoxal-bis-(Guanylhydrazone) and Aliphatic Derivatives.- A. Effects on Experimental Tumors.- I. Tumor Sensitivity.- II. Structure-Activity Relationships.- III. Combination Treatments.- B. Effects on Microorganisms.- I. Bacteria and Protozoa.- II. Viruses.- C. Pharmacological Studies.- I. Toxicological Effects.- II. Disposition and Cellular Uptake.- III. Therapeutic Effects in Man.- D. Mechanism of Action.- I. Relationships to Spermidine.- II. Relationships to Nucleic Acids.- III. Relationships to Mitochondrial Functions.- 4,4?,-Diacetyl-Diphenyl-Urea-bis(Guanylhydrazone) (DDUG) and Other Aromatic bis- (Guanylhydrazones).- A. Effects on Experimental Tumors.- I. Spectrum of Tumor Sensitivity.- II. Structure-Activity Relationships.- III. Combination Treatments.- B. Pharmacological Studies.- I. Toxicological Effects.- II. Disposition and Cellular Uptake.- C. Mechanism of Action.- Conclusions.- References.- 72 Clinical and Pharmacologic Effects of Hydroxyurea.- Fate and Distribution.- Teratogenic Effects.- Mechanism of Action.- Cell Cycle Specificity..- Conclusions.- References.- 73 ?-(N)-Heterocyclic Carboxaldehyde Thiosemicarbazones.- Antineoplastic Activity.- A. Correlation of Ring Substitution with Tumor-Inhibitory Potency.- B. Correlative Studies of Chelating Potential with Antitumor Activity...- C. Combination Chemotherapy.- D. Clinical Studies.- Antiviral Activity.- Distribution and Metabolism.- Biochemical Mechanism of Action.- Conclusions.- References.- 74 1-(o-Chlorophenyl)-1-(p-Chlorophenyl)-2,2-Dichloroethane (o,p?-DDD), an Adrenocorticolytic Agent.- Pharmacology.- A. Absorption.- B. Distribution.- C. Metabolism.- D. Excretion.- Effects on Adrenocortical Tissue.- A. Histologic and Ultrastructural Changes.- B. Effects on Steroid Production.- C. Mechanism of Action of o,p'-DDD.- Extra-Adrenal Effects.- A. Effects on Steroid Metabolism.- B. Effects on Drug Metabolism.- C. Effects on Thyroxine Binding Globulin.- Clinical Studies.- A. Patient Population.- B. Drug Treatment.- C. Clinical Results.- D. Side Effects and Toxicity.- References.- 75 The Phthalanllides.- Tumor-Inhibitory Activity and Toxicity.- Metabolism.- Biochemical Mechanism of Action.- Conclusions.- References.- 76 Platinum Compounds.- Tumor-Inhibitory Activity.- Toxicity of Platinum Compounds.- Distribution of Tumor-Inhibitory Platinum Compounds.- Biochemical Mechanism of Action.- Addendum.- References.- 77 Metal Chelates of 3-Ethoxy-2-Oxobutyraldehyde bis (Thiosemicarbazone), H2KTS.- Antineoplastic Activity of H2KTS.- Metal Chelation and Antitumor Activity of H2KTS (Activity of Cu(II) KTS and ZnKTS).- Studies on the Mechanisms of Action of Cu(II)KTS.- References.- 78 Phleomycin and Bleomycin.- General Properties.- A. Composition.- B. Physical Properties.- C. Spectral Features.- D. Permeability.- E. Range of Biological Activity.- Actions.- A. Selective Inhibition of DNA Synthesis.- B. Receptivity of Target Sites.- C. Selective Inhibition of Cell Division.- D. Inhibition of Replicative RNA.- E. Arrest of Transcription.- F. Toxicity.- G. Effects on Genes.- Reactions with DNA and Considerations of Mechanisms.- A. Reactions.- B. Polyphleomycin Model.- C. Cleaving of DNA.- Bleomycin in Cancer Chemotherapy.- References.- 79 Pharmacology of Newer Antineoplastic Agents.- Guanazole.- Gallium.- Hycanthone.- Ellipticine and 9-Methoxyellipticine.- Alanosine.- Rifamycin SV and Derivatives.- Tilorone Hydrochloride.- ICRF159.- Isophosphamide.- Cyclocytidine.- References.- Addendum to Cytotoxic Analogs of Pyridine Nucleotide Coenzymes.- Author Index.