Main description:

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 em ployed 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 estab lished agents has continued to expand, and has permitted rational drug design to playa significantly greater role in a process which, in its early years, depended almost completely upon empirical and fortuitous observations.

Contents:

I Table of Contents.- Section A: General Considerations: Antineoplastic Agents.- 1 Agents of Choice in Neoplastic Disease.- General Remarks on Criteria for Drug Choice.- The Tumor.- The Drug.- The Patient.- Physician Factors.- Choice of Drugs for Treatment of Specific Types of Cancer.- Choice of Drugs for Highly Responsive (Large Growth Fraction) Tumors.- Drugs of Choice for Patients with Tumors that are Partially Responsive to Chemotherapy (Small Growth Fraction Tumors).- Drugs with Some Activity in Patients with Tumors that have Slight or Negligible Drug Responsiveness.- Conclusions.- References.- 2 Evaluation of Antineoplastic Activity: Requirements of Test Systems.- Selection and Acquisition of Agents for Screening.- The Choice of Screening Systems.- Determination of Drug Activity.- Drug Evaluation and Development.- Some Principles of Screening and Drug Evaluation.- Preclinical Toxicology.- Clinical Evaluation.- References.- 3 Rational Design of Alkylating Agents.- General Principles of Rational Design of Agents.- A. Exploitation of Physico-Chemical Characteristics.- I. Solubility and Partition Coefficients.- II. Derivatives with Active Transport Potentialities.- III. Derivatives with Tissue Specific Affinity.- B. Exploitation of Differences in Chemical Reactivity.- I. Highly Reactive Agents for Intra-Arterial Infusion.- II. Mechanistic Differences.- III. Chemical Reactivity Influenced by Tissue pH.- IV. Chemical Reactivity Influenced by Tissue Redox Potential.- C. Exploitation of Differences in Enzyme Constitution of Tissues.- I. Agents Modified by Hydrolytic Enzymes.- II. Agents Activated by Reducing Enzymes.- III. Agents Activated by Oxidative Enzymes.- Conclusions.- References.- 4 Rational Design of Folic Acid Antagonists.- Historical Aspects.- Structural Analogs of Pteroylglutamate.- Folate Antagonists which are not Structural Analogs of Reduced Pteroylglutamate.- Structural Analogs of Reduced Pteroylglutamates.- Conclusions.- References.- 5 Rational Design of Purine Nucleoside Analogs.- Chemistry.- A. Ring Analogs of Purines.- I. Azapurines.- II. Pyrazolopyrimidines.- III. Deazapurines.- B. Unnatural Purines and Their Nucleosides.- I. Adenine Analogs.- 1. 2-Substituted Adenines.- 2. 8-Substituted Adenosines.- 3. 9-D-Furanosyladenines.- 4. Other 6-Substituted Purines.- II. 6-Thiopurines.- 1. 6-Mercaptopurine and Thioguanine.- 2. Nucleosides and Derivatives.- 3. S-Substituted Derivatives.- 4. Other C- and N-Substituted Derivatives.- 5. Oxidation Products.- 6. Selenium Analogs.- III. Purines Containing Chemically Reactive Groups.- References.- 6 Rational Design of Pyrimidine Nucleoside Analogs.- Design of Pyrimidine Nucleosides as Cytotoxic Agents.- References.- 7 Basic Concepts of Cell Population Kinetics.- The Identification of the Proliferative State of Cells.- The Kinetic Parameters of Cell Populations.- Age Distribution of Cells.- Measurement of Turnover Time and Potential Doubling Time.- Measurement of the Intermitotic Time and Duration of the Constituent Phases.- Measurement of Growth Fraction.- Measurement of Cell Loss.- Cell Population Kinetics of Normal Tissues.- Cell Population Kinetics of Tumors.- References.- 8 Clinical Applications of Cell Cycle Kinetics.- Classification of Tumors Based on Response to Treatment.- Integration of Cytokinetic Strategems with other Therapeutic Considerations.- Hematopoietic Tumors.- A. Acute Leukemia.- I. General Characteristics and Potential Curability.- II. Cytokinetic Considerations.- III. Application of Cytokinetic Principles to Treatment.- IV. Sequential Chemotherapy.- V. Synchronization.- VI. Recruitment of Dormant Cells.- B. Chronic Leukemias.- C. Lymphomas.- D. Multiple Myeloma.- Solid Tumors.- A. Cytokinetic Considerations.- B. Effects of Radiation and Chemotherapy.- C. Combined Methods of Treatment.- Future Developments.- A. Immunotherapy.- B. Inducing Tumor Cells to Differentiate.- C. Control of Cell Division.- Conclusions.- References.- 9 Metabolic Events in the Regulation of Cell Reproduction.- The Cell Replication Cycle.- Biochemical Events in Cell Reproduction.- Enzyme Activities in the Cell Cycle.- RNA in the Cell Cycle.- DNA-Binding Proteins.- Conclusions.- References.- 10 Site of Action of Cytotoxic Agents in the Cell Life Cycle.- Age-Responses to Various Agents.- Application of Age-Responses to the Design of Chemotherapeutic Regimes.- References.- 11 Pharmacokinetic Models for Antineoplastic Agents.- The Utility of Pharmacokinetics.- Model Types and Kinetic Principles.- A. One Compartment Model.- B. Two Compartment Open Model.- C. Multicompartment Models.- Prediction by Models.- Problems of Variability.- References.- 12 Absorption, Distribution, and Excretion of Antineoplastic and Immunosuppressive Agents.- Cell Membrane Barriers.- A. Simple Diffusion.- B. Filtration.- C. Specialized Transport.- Drug Routes of Administration.- A. Oral Route.- B. Parenteral Route.- C. Percutaneous Route.- D. Other Routes.- Drug Distribution.- A. Plasma Protein Binding.- B. Redistribution.- Drug Excretion.- Conclusions.- References.- 13 Transport of Antineoplastic Agents.- Modes of Cellular Uptake.- Effect of Cell Size and Cell Generation Time.- A. Cell Size.- B. Cell Generation Time.- Uptake of Individual Agents.- A. Steroids.- I. Cholesterol.- II. Corticosteroids.- III. Estradiol.- B. Purine and Pyrimidine Bases.- I. Purines.- II. Pyrimidines.- C. Purine and Pyrimidine Nucleosides.- D. Purine and Pyrimidine Nucleotides.- E. Folate Analogs.- I. Concentration Versus Uptake.- II. Intracellular Accumulation of Free Methotrexate.- III. Energetics of Methotrexate Uptake.- IV. Methotrexate Efflux.- V. Inhibitors of Energy Metabolism.- VI. Effects of other Inhibitors.- VII. Uptake of other Folate Analogs.- VIII. Comparison of Cells with Respect to Methotrexate Uptake.- IX. The Mode of Uptake of Methotrexate.- X. Dihydrofolic Acid Reductase Inhibitors with Improved Uptake.- F. Alkylating Agents.- I. Nitrogen Mustard (HN2).- II. Other Alkylating Agents.- G. Guanylhydrazones and Phthalanilides.- I. Methylglyoxal-bis-Guanylhydrazone (CH3-G).- II. 4,4?-Diacetyl-Diphenyl-Urea-bis-Guanylhydrazone (DDUG).- III. Phthalanilides.- Conclusions.- References.- 14 Metabolism of Cancer Chemotherapeutic Agents via Pathways Utilized by Endogenous Substrates.- Folate Antagonists.- Thiopurines.- A. 6-Mercaptopurine.- B. 6-Thioguanine.- C. 6-Methylthiopurine (6-MMP) and 6-MMP Eibonucleoside.- D. Azathioprine.- E. Formycin A and B.- 5-Fluorouracil and Related Fluoropyrimidines.- Iododeoxyuridine.- l- ?-D-Arabinosylcytosine.- Hydroxyurea.- Vinca Alkaloids.- 5-Azacytidine.- Azaserine.- References.- 15 Metabolism of Cancer Chemotherapeutic Agents via Pathways Utilized by Xenobiotics.- Specificity of Drug-Metabolizing Enzymes.- Mechanism of Oxidation of Antineoplastic Agents.- Reductive Mechanisms.- Hydrolytic Enzyme Systems.- Conjugation Reactions.- A. Glucuronides.- B. Sulfates.- C. Amino Acid Conjugations.- D. N-Hydroxy Conjugations.- E. Miscellaneous Conjugation Reactions.- Factors Influencing the Metabolism of Anticancer Agents.- A. Enzyme Induction.- B. Species Differences.- C. Presence of Neoplastic Disease.- D. Pretreatment with Antitumor Drugs.- Drug Latentiation as Affected by Drug Metabolism.- Identification of Antineoplastic Drugs in Body Tissues and Fluids.- Spontaneous Reactions of Antineoplastic Agents.- Noncancer Uses of Anticancer Agents.- Metabolism of Specific Antineoplastic Agents.- A. Alkylating Agents.- I. Nitrogen Mustard (Mechlorethamine, HN2, Mustargen).- II. Cyclophosphamide (Cytoxan, Endoxan, Procytoc, CTX).- III. Aziridine Mustards.- IV. N-(3-OxapentamethyleneJ-N?N?-diethylenethiophosphoramide (OPSPA).- V. Methanesulfonate (Busulfan, Myleran, GT-41, 1,4-dimethanesulfonyloxybutane).- VI. Nitrosoureas.- B. Miscellaneous Compounds.- I. Procarbazine (Methylhydrazine, MIH, Natulan, Matulan).- II. o,p?-DDD (o,p?-Dichlorodiphenyldichloroethane, Mitotane, Lysodren).- III. Mitomycin.- IV. Puromycin.- V. 6-Methylthiopurine.- References.- 16 Theoretical Considerations in the Chemotherapy of Brain Tumors.- Administration of Drug Through the Vascular System.- A. Rate of Perfusion of the Tumor.- B. Activity Gradients.- C. The Blood-Brain Barrier.- D. Diffusion Through Extracellular Fluid.- E. Cellular Uptake.- F. Timing of Injections.- G. Local Infusion with Antidotes.- Models of Drug Uptake.- Intrathecal Administration of Antineoplastic Drugs.- Comment.- Conclusions.- References.- 17 The Constancy of the Product of Concentration and Time.- Formulations of the Relationship of Concentration and Time and Biological Response.- Relationships of Dose, Drug Metabolism Rates, Drug Plasma or Tissue Levels and Pharmacological Response in Various Species.- Conclusions.- References.- 18 Biochemical Aspects of Selective Toxicity.- Selectivity Due to Differences in the Concentration of Drug at the Biochemical Site of Action.- A. Entry into Cells.- B. Conversion to Active Forms.- C. Drug Catabolism.- D. Loss of Drug from Cells.- Selectivity Due to Differences in the Interaction of Drugs with Their Biochemical Targets.- A. Effective Concentration of the Target.- B. Affinity of the Target for the Drug.- C. Mode of Binding.- D. Concentration of Protecting Metabolites.- Selectivity Due to Differences in the Effects of Drug-Target Interaction on Cell Growth.- A. Completeness of Inhibition.- B. Importance of the Target.- C. Amounts of Accumulated Products.- D. Repair or Recovery.- Selectivity Due to Differences in the Effects of Inhibition of Cell Growth on Cell Viability and Cell Loss.- Conclusions.- References.- 19 Mechanisms of Resistance.- Origins of Drug Resistance.- A. Chromosomal Changes.- B. Gene Mutations.- C. Stable Changes in Phenotypic Expression.- D. Mechanisms for Transmission of Resistance.- E. Drug-Resistant Cells as Tools in Genetic Research.- F. The Problem of Drug Resistance.- G. Other Aspects of the Problem of Drug Resistance.- H. Cell Cycle Kinetics and Drug Resistance.- Mechanisms of Resistance to Folic Acid Analogs.- A. Dihydrofolate Reductase Activity and Folate Analogs.- B. Resistance to Folate Analogs Accompanied by Increased Levels of Dihydrofolate Reductase.- C. Multiple Forms of Dihydrofolate Reductase in Cells Resistant to Folate Analogs.- D. Altered Enzyme in Cells Resistant to Folate Analogs.- E. Cofactor Binding to Dihydrofolate Reductases in Relation to Drug Resistance.- F. Decreased Uptake of Drug as a Mechanism of Resistance to Methotrexate.- G. Intracellular Drug Alteration as a Mechanism of Resistance to Folate Antagonists.- H. Correlation of Changes in Biochemical Parameters with Response to Methotrexate.- Mechanisms of Resistance to Purine and Pyrimidine Analogs.- A. Decreased Activity of Purine and Pyrimidine Nucleotide-Forming Enzymes.- I. 6-Mercaptopurine.- II. 6-Thioguanine.- III. 6-Methylmercaptopurine Ribonucleoside.- IV. 6-Azauracil.- V. 5-Fluorouracil.- VI. 5-Fluoro-2?Deoxyuridine.- VII. Arabinosylcytosine.- VIII. 5-Azacytidine.- IX. 5-Aza-2?Deoxycytidine.- B. Failure of Resistant Cells to Metabolize an Initially Formed Nucleotide to a More Inhibitory Form or Failure to Incorporate an Analog Nucleotide into Polynucleotides.- C. Alteration of the Target Enzyme in Resistant Cells in Such a Way that it Becomes Less Sensitive to the Analog Nucleotide.- D. Increased Degradation of the Analog Itself or of the Analog Nucleotide.- E. Failure of the Analog to Gain Entry into Resistant Cells (or Failure of the Analog to Gain Access to the Site of its Activation within the Cell).- F. Increased Production of Metabolites Capable of Overcoming the Inhibitory Effects of the Analog.- G. Other Mechanisms of Resistance to Purine and Pyrimidine Analogs.- Resistance to Alkylating Agents.- A. Altered Cell Permeability.- B. Increased Cellular Concentration of Protective Agents, Such as Sulfhydryl Compounds.- C. Increased Capacity of Resistant Neoplasms for Repair of DNA Damaged by Alkylation.- Resistance to Other Agents.- A. L-Asparaginase.- B. Steroid Hormones.- C. Anticancer Agents of Complex Structure that bind to Cellular Components.- Conclusions.- References.- 20 Combination Chemotherapy: Basic Considerations.- Some Principles of Combination Drug Evaluation.- Therapeutic Synergism Resulting from Decreased Host Toxicity without Concomitant Decrease in Effectiveness Against the Tumor.- A. Differential Protection of the Host by a Metabolite Employed in Conjunction with an Antimetabolite.- B. Differential Protection of the Host Against Toxicity of an Antitumor Agent by a Therapeutically Inactive Drug.- C. Differential Protection of the Host Against an Antitumor Agent by a Second Therapeutically Active Drug.- Therapeutic Synergism Resulting from Selective Increase in Antitumor Toxicity Using Combinations of Individually Active Agents.- Attempts to Improve Therapy by Altering the Concentration (C) and Duration of Effectiveness (T) of an Antitumor Agent.- Schedule Dependency in Combination Chemotherapy.- Sequential Combination Chemotherapy.- The Dosage Ratio in Drug Combinations.- Biochemical Rationale in the Choice of Drug Combinations.- A. Combinations of Cytosine Arabinoside (ara-C) and Inhibitors of Ribonucleoside Diphosphate Reductase.- B. Combination Chemotherapy of Mouse Leukemias Using Glutamine Analogs and L-Asparaginase.- Use of Drug Combinations to Overcome Resistance to Treatment.- Combination Chemotherapy of Meningeal Leukemia.- Combination Chemotherapy of Spontaneous AKR Lymphoma.- Chemotherapy Plus Immunotherapy.- Surgery and Chemotherapy (Surgical-Adjuvant Therapy).- Conclusions.- References.- 21 Combination Chemotherapy: Clinical Considerations.- Molecular Biology.- A. Sequential Biochemical Blockade.- B. Concurrent Biochemical Blockade.- C. Complementary Blockade.- Pharmacology.- Cytokinetics.- Drug Resistance.- Biologic Approaches.- Toxicologic Approaches.- Clinical Combination Chemotherapy.- A. Remission Induction.- B. Maintained Remission.- C. Duration of Unmaintained Remission.- D. Maintenance Therapy.- E. Reinduction During Maintenance.- Acute Lymphocytic Leukemia of Children.- Unmaintained Remission for Acute Lymphocytic Leukemia of Childhood.- Survival and Cure.- Acute Myelogenous Leukemia of Adults.- Hodgkin's Disease.- Non-Hodgkin's Lymphoma.- Multiple Myeloma.- Solid Tumors.- A. Introduction.- B. Breast Cancer.- C. Other Solid Tumors.- Conclusions.- References.- 22 Tests Predictive of Cytotoxic Activity.- Sensitivity Testing.- Conclusions.- References.- 23 Metabolic Changes Induced by Ionizing Radiations.- Effects of Ionizing Radiations on Biological Molecules.- A. Nucleic Acids and Their Substituents.- B. Proteins.- C. Lipids and Carbohydrates.- D. Macromolecular Complexes.- E. Summary of Molecular Effects.- Subcellular and Early Metabolic Changes.- A. The Synthesis of DNA and its Precursors.- B. RNA Synthesis.- C. Protein Synthesis.- D. Histones.- E. Nuclear Phosphorylation.- F. Oxidative Phosphorylation.- G. Sulfhydryl Compounds.- H. Transport Phenomena.- Whole-Body Metabolic Changes.- A. Pertinent Tissue Pathology.- B. Metabolic Changes Due to Intestinal Effects.- C. Metabolic Changes Associated with Effects on Lymphatic Tissues.- D. Metabolic Changes Associated with Bone-Marrow Effects.- E. Some General Metabolic Effects.- Conclusions.- References.- 24 Radiation Research: Survival Kinetics.- A. Cell Killing.- B. Loss of Proliferative Capacity.- C. Postirradiation Growth and Cell Disintegration.- Loss of Proliferative Capacity.- A. Theoretical Considerations.- B. In Vitro Determination of Dose-Survival Curves.- C. In Vivo Determinations of Dose-Survival Curves.- D. Modulation of the Dose-Survival Response.- Postirradiation Growth and Cell Disintegration.- A. Mitotic Delay.- B. Cell Disintegration (Physiological Death).- C. Other Kinetic Parameters.- Conclusions.- References.- 25 Clinical and Laboratory Investigation of Combination Radiation and Chemical Therapy.- Sensitizing and Additive Effects.- Alkylating Agents.- Actinomycin D.- Methotrexate.- Purine Analogs.- Fluorinated Pyrimidines.- Hydroxyurea.- Other Halogenated Pyrimidine Analogs.- Conclusions.- References.- 26 Tumor Immunotherapy.- Active Immunotherapy.- A. Non-Specific.- B. Specific.- Passive Immunotherapy (Serotherapy).- Adoptive Immunotherapy.- A. Syngeneic.- B. Allogeneic.- Adoptive Immunotherapy as an Adjunct to Whole Body x-Irradiation (Adoptive Radio-immunotherapy).- A. Syngeneic.- B. Allogeneic.- Adoptive Immunotherapy as an Adjunct to Chemotherapy (Adoptive Chemoimmunotherapy).- References.- Section B: General Considerations: Immunosuppressive Agents.- 27 Evaluation of Immunosuppressive Agents.- Synthesis of Antibody.- A. Testing in Animals.- B. Antibodies to Allogeneic Tumor Cells.- C. In Vitro Culture Methods.- D. Investigations in Man.- Cellular Immunity (Delayed Hypersensitivity).- A. Testing in Animals.- B. In Vitro Methods.- C. Investigations in Man.- D. Effects upon "Nonspecific" Aspects of Inflammation.- Clinical Trials of Immunosuppressive Agents in Autoimmune Diseases.- References.- 28 Immunosuppressive Agents.- Relationship of Chemical Immunosuppression to the Normal Immune Response.- Interrelationship of Chemotherapy, Immunosuppression, and Prognosis During the Treatment of Human Disease.- Comparative Studies of Immunosuppression by Different Agents.- A. Alkylating Agents.- B. Purinethiols and Purinethiol Nucleosides.- C. Folic Acid Antagonists.- D. Cytosine Arabinoside and Related Nucleoside Analogs.- E. Vinca Alkaloids.- F. Actinomycin D and other Antibiotics.- G. Immunosuppressive Enzymes.- H. Miscellaneous Agents.- Conclusions.- References.- 29 Clinical Utility of Immunosuppressive Agents.- Complications of Immunosuppressive Therapy.- A. Infection.- B. Cytogenetic Changes.- C. Malignancy in the Immunosuppressed Patient.- D. Other Complications Associated with Immunosuppressive Drugs.- Immunosuppressive Drugs in Human Transplantation.- A. Kidney.- B. Liver.- C. Heart and Lung.- D. Bone Marrow.- Immunosuppressive Drugs in Autoimmune Disease.- A. Autoimmune Blood Disease.- I. Autoimmune Hemolytic Anemia.- II. Idiopathic Thrombocytopenic Purpura.- III. Hyperglobulinemic Purpura.- B. Autoimmune Renal Disease.- I. Systemic Lupus Erythematosus (SLE).- II. Glomerulonephritis.- III. Goodpasture's Syndrome.- C. Gastrointestinal Disease.- I. Ulcerative Colitis.- II. Regional Enteritis.- III. Liver Disease.- D. Wegener's Granulomatosis.- E. Collagen Diseases.- I. Rheumatoid Arthritis.- II. Dermatomyositis-Scleroderma.- F. Ocular Disease.- G. Skin Disease.- I. Pemphigus.- H. Neuromuscular Disease.- I. Asthma.- Conclusions.- References.- Author Index.