Antineoplastic and immunosuppressive agents

Author(s)

• Sartorelli, Alan C.
• Johns, David G.

Bibliographic Information

Antineoplastic and immunosuppressive agents

editors, Alan C. Sartorelli and David G. Johns

（Handbuch der experimentellen Pharmakologie. Heffter-Heubner, [Bd.] 38）

Springer-Verlag, 1974-75

• part 1 : gw
• part 2 : gw
• part 1 : us
• part 2 : us

Note

Includes bibliographies and index

part 1 / contributors, R.C. Bagai ... [et al.]

part 2 / contributors, H.T. Abelson ... [et al.]

Description and Table of Contents

Volume

part 1 : gw ISBN 9783540064022

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.

Table of 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'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"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"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.- Conclu

Volume

part 2 : gw ISBN 9783540066330

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 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.

Table of Contents

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.

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Details

• NCID: BA06977931
• ISBN:
  • 3540064028
  • 3540066330
  • 0387064028
  • 0387066330
• LCCN: 73010507
• Country Code: gw
• Title Language Code: eng
• Text Language Code: eng
• Place of Publication: Berlin
• Pages/Volumes: 2 v.
• Size: 25 cm
• Classification:
  • LCC : QP905
  • LCC : RC271.C5
  • DC : 615/.1/08 s
  • DC : 616.9/92/061
• Subject Headings:
  • LCSH : Antineoplastic agents
  • LCSH : Immunosuppressive agents
• Parent Bibliography ID:
  • BA03784410