Chemotherapy

ISBN-13: 9781461566304 / Angielski / Miękka / 2012 / 666 str.

Frederick Becker

Opis

The promise of chemotherapeutic control in the field of oncology seemed, in the beginning, no less bright than it had proven in the field of bacterial disease, and, therefore, its failures were felt all the more. Despite the serendipitous discoveries and inspired insights which tantalized us with striking remissions, or the rare tumors which proved to be fully susceptible to a given agent, in the main, there has been either total failure or a painfully slow acquisition of an armamentarium against a limited number of malignancies. To expect more, however, was the result of ignorance of the malignant cell, for, as has been described in the previous volumes of this series, the exploitable differences between malignant and normal cells are few or undiscovered. "Differences" is the "numerator" in this formula, but "exploitable" is the operational term, for, although a great number of differences bet\een normal and malignant cells have been described, rarely are these differences observed in a vital metabolic pathway or a crucial macromolecu- lar structure. Essentially, the basic metabolic pathways and nutritional require- ments for: lOrmal and malignant cells are the same, resulting in the fact that no chemotherapeutic agent can successfully inhibit a function in the majority of malignant cells without adversely affecting a similar function in the normal cell. It was, therefore, naive to expect a "magic bullet" which would select the malignant cell and destroy it.

Spis treści

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.