Antineoplastic and Immunosuppressive Agents

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