Table of Contents

General Principles of Chemotherapy.- 1 Factors That Influence the Therapeutic Response.- 1. Introduction.- 2. Tumor Factors.- 2.1. "Specific" Responsiveness to Drugs.- 2.2. Location.- 2.3. Conclusions.- 3. Host Factors.- 3.1. Prior Therapy.- 3.2. General Health.- 3.3. Support Facilities.- 4. Therapeutic Goals.- 5. New Problems.- 5.1. Immunosuppressive and Carcinogenic Effects.- 5.2. Specific Drug Effects.- 5.3. Summary.- 6. Conclusion.- 7. References.- 2 Applications of Cell Kinetic Techniques to Human Malignancies.- 1. Introduction.- 2. Currently Available Kinetic Techniques.- 2.1. Measurements of Tumor Size.- 2.2. Measurements of Tumor Size from Biological Markers.- 2.3. Mitotic Index.- 2.4. Stathmokinetic Methods.- 2.5. Labeling Index.- 2.6. Percentage Labeled Mitosis.- 2.7. Grain-Count-Halving.- 2.8. Double-Labeling Techniques.- 2.9. Growth Fraction.- 2.10. Potential Doubling Time and Cell Loss Factor.- 2.11. DNA Distribution Techniques.- 2.12. Xenografts.- 3. Kinetics of Specific Tumors.- 3.1. Acute Leukemia.- 3.2. Chronic Myelocytic Leukemia.- 3.3. Chronic Lymphocytic Leukemia.- 3.4. Multiple Myeloma.- 3.5. Lymphomas.- 3.6. Breast Carcinoma.- 3.7. Colon Carcinoma.- 3.8. Lung Carcinoma.- 3.9. Head and Neck Cancer.- 3.10. Malignant Melanoma.- 3.11. Miscellaneous Tumors.- 4. Conclusions.- 5. References.- 3 Toxicity of Chemotherapeutic Agents.- 1. Introduction.- 2. Gastrointestinal Toxicity.- 3. Cutaneous Reactions.- 4. Fever.- 5. Alopecia.- 6. Hepatic Toxicity.- 7. Pulmonary Toxicity.- 8. Cardiac Toxicity.- 9. Renal Toxicity.- 10. Coagulopathy.- 11. Nervous System Toxicity.- 12. Effects on Serum Electrolytes.- 13. Sterility.- 14. Immunosuppression.- 15. Bone Marrow Toxicity.- 16. Miscellaneous Toxic Effects.- 17. Second Malignancies.- 18. References.- 4 Clinical Aspects of Resistance to Antineoplastic Agents.- 1. General Considerations.- 2. Basic Mechanisms of Resistance.- 2.1. Natural Drug Resistance.- 2.2. Acquired Drug Resistance.- 3. Drug Resistance in Human Leukemia.- 3.1. Thiopurines.- 3.2. Cytosine Arabinoside.- 3.3. Methotrexate.- 3.4. Daunorubicin and Adriamycin.- 3.5. L-Asparaginase.- 3.6. Corticosteroids.- 4. Drug Resistance in Cancers Other than Leukemia.- 4.1. Alkylating Agents.- 4.2. 5-Fluorouracil.- 4.3. Sex Hormones and Breast Cancer.- 5. Ways to Overcome the Problem of Drug Resistance.- 5.1. Change the Method of Drug Administration.- 5.2. Change the Drug Preparation.- 5.3. Use Drug Combinations and Combined Modalities.- 5.4. Treat Earlier in the Disease-Adjuvant Therapy.- 6. Exploitation.- 7. Conclusion.- 8. References.- 5 Adjunctive Chemotherapy.- 1. Introduction.- 2. Experimental Evidence from Animal Models.- 3. Clinical Applications of Adjuvant Chemotherapy.- 3.1. Breast Cancer.- 3.2. Lung Cancer.- 3.3. Gastrointestinal Cancer.- 3.4. Ovarian Cancer.- 3.5. Testicular Cancer.- 3.6. Head and Neck Cancer.- 3.7. Brain Tumors.- 3.8. Osteogenic Sarcoma.- 3.9. Ewing's Sarcoma.- 3.10. Wilms's Tumor.- 3.11. Rhabdomyosarcoma.- 3.12. Neuroblastoma.- 4. Conclusions.- 5. References.- 6 Principles of Combination Chemotherapy.- 1. Introduction.- 2. General Principles.- 2.1. Drugs Individually Effective Against the Tumor.- 2.2. Minimal Overlapping Toxicities.- 2.3. Pharmacological Considerations.- 2.4. Cytokinetic Considerations.- 2.5. Schedule Dependency.- 2.6. Miscellaneous Considerations.- 2.7. Combination vs. Single-Agent Chemotherapy: Selected Examples.- 3. References.- 7 Intraarterial Chemotherapy.- 1. Introduction and History.- 2. Pharmacology.- 3. Technical Considerations and Complications.- 4. Results of Infusions in Specific Locations.- 4.1. Liver.- 4.2. Head and Neck.- 4.3. Other Sites.- 5. Future Considerations.- 6. References.- 8 Treatment of Malignant Disease in Closed Spaces.- 1. Malignant Pleural Effusions.- 1.1. Pathogenesis.- 1.2. Diagnosis.- 1.3. Therapy.- 2. Malignant Peritoneal Effusions.- 2.1. Pathogenesis.- 2.2. Diagnosis.- 2.3. Therapy.- 3. Malignant Pericardial Effusions.- 3.1. Pathogenesis.- 3.2. Diagnosis.- 3.3. Therapy.- 4. Involvement of the Meningeal Space by Malignant Diseases.- 4.1. Pathogenesis.- 4.2. Diagnosis.- 4.3. Therapy.- 5. References.- 9 Supportive Care in the Cancer Patient.- 1. Introduction.- 2. Blood Loss.- 2.1. General Aspects.- 2.2. Nonhemorrhagic Red Cell Loss.- 2.3. Hemorrhage.- 2.4. Approach to the Patient with Blood Loss.- 3. Infection.- 3.1. General Comments.- 3.2. Oncology and the Infectious Disease Service.- 3.3. Predisposing Factors to Infection.- 3.4. Prophylaxis of Infection.- 3.5. Management of Infection.- 4. References.- Chemotherapeutic Agents.- 10 Alkylating Agents and the Nitrosoureas.- 1. Introduction.- 1.1. History.- 1.2. Classification of Alkylating Agents and Nitrosoureas.- 1.3. Purpose of This Review.- 2. Mechanism of Action.- 2.1. Biological Effects of Alkylating Agents and Nitrosoureas.- 2.2. Chemistry of Alkylation.- 2.3. DNA as the Primary Target of Alkylation.- 3. Formation of the Alkylating Species.- 3.1. General.- 3.2. Cyclophosphamide.- 3.3. Nitrosoureas.- 4. Distribution and Cellular Uptake of Agents.- 5. Modifications of DNA.- 5.1. Sites of Reaction.- 5.2. Amplification and Repair of Damage.- 5.3. Significance of DNA Modifications.- 6. Role of Alkylating Agents and Nitrosoureas in Chemotherapy.- 7. Summary.- 8. References.- 11 Purine Antagonists.- 1. Introduction.- 2. 6-Mercaptopurine.- 2.1. History.- 2.2. Chemistry.- 2.3. Pharmacology.- 2.4. Metabolism and Metabolic Effects.- 2.5. Derivatives.- 3. 6-Thioguanine.- 3.1. History.- 3.2. Chemistry.- 3.3. Pharmacology.- 3.4. Metabolism and Metabolic Effects.- 3.5. Derivatives.- 3.6. Clinical Uses.- 4. Allopurinol.- 5. Arabinosyl-6-Mercaptopurine.- 6. Arabinosyladenine.- 6.1. History.- 6.2. Chemistry.- 6.3. Metabolism and Metabolic Effects.- 6.4. Pharmacology.- 6.5. Derivatives.- 6.6. Clinical Uses.- 7. Glutamine Antagonists.- 7.1. History.- 7.2. Chemistry.- 7.3. Pharmacology.- 7.4. Metabolism and Metabolic Effects.- 7.5. Clinical Uses.- 8. References.- 12 Pyrimidine Antagonists.- 1. Introduction.- 1.1. Logic Behind the Development and Use of Metabolic Antagonists.- 1.2. Why Logic Can Fail.- 2. Pyrimidine Derivatives That Act as Antimetabolites.- 2.1. Cytosine Arabinoside.- 2.2. 6-Azauracil and Azauridine.- 2.3. 5-Azacytidine.- 2.4. 3-Deazauridine.- 2.5. 5-Fluorouracil, 5-Fluorodeoxyuridine, and 5-Fluorouridine.- 2.6. Other 5-Alkyl Pyrimidines.- 3. Improving the Effectiveness of the Pyrimidine Antagonists by Combination Therapy.- 4. Prospects for the Future.- 5. References.- 13 Folate Antagonists.- 1. Mode of Action of Folate Antagonists: Relationship between Inhibition of Dihydrofolate Reductase and Cytotoxicity.- 2. Toxicities Unrelated to Inhibition of Dihydrofolate Reductase.- 3. Resistance to Folate Antagonists.- 4. Clinical Applications of Folate Antagonists.- 5. References.- 14 Plant Alkaloids.- 1. Introduction.- 2. Metaphase-Arresting Agents: Colchicine, the Vinca Alkaloids, Podophyllotoxin, and Griseofulvin.- 2.1. Occurrence.- 2.2. Biological Activity.- 2.3. Structure-Activity Relationships.- 2.4. Mechanism of Action.- 2.5. Metabolism and Distribution.- 2.6. Clinical Aspects.- 3. Ellipticine Derivatives.- 3.1. Occurrence and Chemistry.- 3.2. Pharmacological Activity.- 3.3. Mechanism of Action.- 3.4. Distribution and Metabolism.- 3.5. Clinical Trials.- 4. Camptothecin.- 4.1. Occurrence and Chemistry.- 4.2. Experimental Antitumor Activity.- 4.3. Biochemical Actions.- 4.4. Structure-Activity Relationships.- 4.5. Distribution and Metabolism.- 4.6. Clinical Trials.- 5. Benzylisoquinoline and Aporphine Alkaloids.- 5.1. Occurrence and Chemistry.- 5.2. Pharmacological Activity.- 5.3. Mechanism of Action.- 5.4. Distribution and Metabolism.- 5.5. Clinical Trials.- 6. Ergot Alkaloids.- 7. Tylophora Alkaloids.- 7.1. Occurrence and Chemical Structure.- 7.2. Mechanism of Action.- 8. Miscellaneous Alkaloids.- 8.1. Acronycine (Acronine).- 8.2. Emetine.- 8.3. ss-Solamarine.- 8.4. Harringtonine.- 8.5. Pyrrolizidine Alkaloids.- 8.6. Narcissus Alkaloids and Fagaronine.- 9. Conclusion.- 10. References.- 15 Antibiotics: Nucleic Acids As Targets in Chemotherapy.- 1. Introduction.- 2. Agents That Alter Nucleic Acid Structure and Function.- 2.1. Intercalators of DNA.- 2.2. Strand Scission of DNA.- 2.3. Covalent Binding.- 2.4. Other Binding.- 3. Inactivators of Nucleic Acid Polymerizing Enzymes.- 3.1. DNA and RNA Polymerases.- 3.2. Tumor Virus Reverse Transcriptase.- 4. Summary and Conclusions.- 5. References.- 16 Enzyme Therapy.- 1. General Considerations of Enzymes as Therapeutic Agents.- 1.1. Comparisons with Other Chemotherapeutic Agents.- 1.2. Optimal Characteristics of Enzymes for Enzyme Therapy.- 1.3. Biological Limitations of Enzyme Therapy.- 2. Nonessential Amino Acid Depletion.- 2.1. Asparagine Depletion.- 2.2. Glutamine Depletion.- 2.3. Arginine Depletion.- 2.4. Tyrosine Depletion.- 2.5. Cystine Depletion.- 2.6. Serine Depletion.- 3. Essential Amino Acid Depletion.- 3.1. Introduction.- 3.2. Phenylalanine Depletion.- 3.3. Methionine Depletion.- 3.4. Other Essential Amino Acid Depletions.- 4. Vitamin Depletion.- 5. Immunologic Enhancement.- 5.1. Neuraminidase.- 5.2. Proteolytic Enzymes.- 5.3. Amino Acid Depletion.- 6. Enzymes That Function Intracellularly.- 6.1. Xanthine Oxidase.- 6.2. Nucleases.- 6.3. Plant and Bacterial Toxins.- 7. The Future of Enzyme Therapy.- 7.1. Selection of Enzymes.- 7.2. Overcoming the Biological Limitations.- 7.3. Conclusion.- 8. References.- 17 Hydrazines and Triazenes.- 1. Introduction.- 2. Hydrazines.- 2.1. Introduction: History, Chemistry, and General Remarks.- 2.2. 1-Methyl-2-p-(isopropylcarbamoyl)benzylhydrazine Hydrochloride (MBH).- 2.3. Hydrazine Sulfate and Miscellaneous Hydrazine Derivatives.- 3. Triazenes.- 3.1. Introduction.- 3.2. Phenyltriazenes.- 3.3. Imidazole Triazenes.- 4. Conclusions and Perspectives.- 5. References.- 18 Antitumor Effects of Interferon.- 1. Introduction.- 2. Effect of Exogenous Interferon and Interferon Inducers on the Development of Tumors in Animals Infected with Oncogenic Viruses.- 2.1. Exogenous Interferon.- 2.2. Interferon Inducers.- 3. Effect of Exogenous Interferon and Interferon Inducers on the Growth of Transplantable Tumors in Animals.- 3.1. Exogenous Interferon.- 3.2. Interferon Inducers.- 4. Effect of Exogenous Interferon and Interferon Inducers on Chemically and Radiation-Induced Neoplasms.- 4.1. Exogenous Interferon.- 4.2. Nonviral Interferon Inducers.- 5. Effect of Exogenous Interferon and Interferon Inducers on Normal Animals.- 5.1. Exogenous Interferon.- 5.2. Interferon Inducers.- 6. On the Mechanisms of the Antitumor Effects of Exogenous Interferon.- 6.1. Virus-Induced Neoplasms.- 6.2. Transplantable Tumors.- 6.3. Spontaneous Neoplasms.- 6.4. Summary.- 7. Use of Exogenous Interferon and Interferon Inducers in the Treatment of Patients with Neoplastic Disease.- 7.1. Exogenous Interferon.- 7.2. Interferon Inducers.- 7.3. Possibilities for Combined Exogenous-Endogenous Interferon Therapy.- 8. Speculations on the Usefulness of Exogenous Interferon in the Treatment of Patients with Malignancy.- 8.1. As an Antitumor Drug.- 8.2. As an Antiviral Drug.- 8.3. Other Uses.- 9. References.- 19 The Physiology of Endocrine Therapy.- 1. Endocrine Feedback and Homeostasis.- 1.1. The Beginnings of Endocrine Therapy.- 1.2. Hormonal Feedback Regulation.- 2. Exploitation of Endocrine Feedback Systems.- 2.1. Therapy-Sensitive Sites in Feedback Systems: Introduction.- 2.2. Reduction in Hormone Levels.- 2.3. Reduction in Hormone Effectiveness.- 2.4. Potential Hormone Utilization.- 3. Potential Cancer Therapeutic Agents-The Prostaglandins and Related Compounds.- 3.1. Source and Structure.- 3.2. Prostaglandin Pharmacology.- 3.3. Prostaglandins and Tumors.- 4. Closing Remarks.- 5. References.- 20 New Anticancer Drug Design: Past and Future Strategies.- 1. Synopsis of Cancer Treatment Research.- 1.1. Three Degrees of Cancer Advancement: Advanced, Previsible, and First Cell.- 1.2. Current Treatment Modalities.- 2. The Biochemical Differences of Cancer Cells.- 3. The Major Mechanisms by Which All Anticancer Drugs with Known Mechanisms of Action Appear to Work.- 3.1. Action at Enzyme Regulatory Centers.- 3.2. Action at Enzyme Catalytic Centers.- 3.3. Blockade of the Enzyme-Substrate Complex by Action on Substrates.- 3.4. Action on Nonenzymic Protein Receptors.- 3.5. Reclassification of the Mechanisms for Drug Design.- 4. Discovery of New Drugs: Screening.- 4.1. Mouse Tumors: Evaluation.- 4.2. 50 New Drugs.- 4.3. Only a Few New Ideas.- 4.4. Success Frequency of Screening.- 5. Physicochemical Correlates of Drug Action: QSAR.- 5.1. Drug Bonding.- 5.2. Quantitative Structure-Activity Relationships.- 5.3. Bioisosterism.- 6. Receptor Targeting and Delivery Approach.- 6.1. The Crossroads: Screening and Serendipity vs. Receptors.- 6.2. Receptor Targeting and Delivery Strategy.- 7. Clinical Considerations in New Drug Design.- 7.1. Unknowns and Variables.- 7.2. Preclinical Toxicology.- 7.3. Selective Toxicities.- 7.4. Evaluation of Current Anticancer Drugs.- 7.5. Cycle-Phase Specificity and Drug Scheduling.- 7.6. Gompertzian Growth and Growth Fractions.- 7.7. Optimizing Single-Drug Use.- 8. Drug Combinations.- 8.1. Millions of Permutations.- 8.2. Multidrug Rationale.- 8.3. Multidrug Success.- 8.4. Unanswered Questions About Multidrug Treatment.- 8.5. Dangerous Drug Combinations.- 9. Past, Present, and Future.- 9.1. Tested and Untested Assumptions.- 9.2. Drug-Design Strategy: Cloudy Crystal Ball.- 10. References.