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.

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…