The study of tumour resistance to anticancer drugs has been the subject of many publications since the initial discovery of the phenomenon by J. H. Burchenal and colleagues in 1950. Many papers have been published since then reporting development of resistance to most of the well-known anticancer agents in many different animal tumour systems, both in vivo and in vitro. Many different mechanisms of resistance have been described, and it is clear that the tumour cell has a wide diversity of options in overcoming the cell-killing activity of these agents. Definition of the magnitude of the phenomenon in the clinic is, however, much more problematical, and it is with this in mind that the initial chapter, seeks to out­ line the problem as the clinicians see it. It appears that the phenomenon of true resistance to a drug, as the biochemist would recognise it, is an important cause of the failure which clinicians experience in treating the disease. The extent of the contribution of this phenomenon to the failure of treatment cannot easily be evaluated at the present time, but it is hoped that the development and application of new and more sophisticated techniques for the analysis of cellular sub­ populations may help to give a more exact estimate and to shed some light on the causes of failure of many of the present therapeutic techniques.

Inhalt

Section I: Concepts of Drug Resistance.- 1 Clinical Setting.- A. Introduction.- B. Resistance - A Clinical Phenomenon?.- C. Disease Assessment.- D. Drug Selection.- E. Measurement of Response.- F. Can Resistance be Quantified Clinically?.- G. Factors Influencing Changes in Tumour Volume.- I. Heterogeneous Target Populations of Tumour Cells.- II. Changes in Histology.- III. Second Malignancy.- IV. Miscellaneous Factors Contributing to Tumour Volume.- H. Influence of Clinically Determined Drug Resistance on Management.- I. Resistance and Toxicity.- II. Resistance and Survival.- References.- 2 Experimental Setting.- A. Introduction.- B. Origins of Resistance.- I. Changes in the Tumor.- 1. Nongenetic Origins.- 2. Genetic Origins.- II. Changes in the Host.- III. Changes in Pharmacological Parameters.- IV. Experimental Systems.- C. Mechanisms of Resistance.- I. Differences in Drug Concentration.- 1. Drug Uptake.- 2. Nucleotide Formation.- 3. Drug Catabolism.- II. Differences in Drug-Target Interaction.- 1. Drug-Enzyme Binding.- 2. Drug-Cell Interaction.- 3. Metabolite Concentrations.- III. Differences in Importance of Biochemical Target.- 1. Recovery from Drug Effects.- 2. Alternative Pathways.- 3. Concentration of Target.- IV. Experimental Systems.- D. Chemotherapy of Resistant Tumors.- I. Cross-Resistance.- II. Collateral Sensitivity.- III. Circumvention of Resistance.- Section II: Modification of Host-Tumor Interaction.- 3 Drug Disposition and Pharmacology.- A. Introduction.- B. Drug Absorption.- C. Distribution.- D. Metabolism.- E. Renal Excretion.- F. Dose.- G. Schedule Dependence.- H. Drug Interactions.- J. Conclusion.- References.- 4 Immunological Changes.- A. Introduction.- B. Tumor-Associated Antigens.- C. Altered Transplantability of Drug-Resistant Tumor Sublines.- I. Tumor Transplantation in Unimmunized Animals.- II. Tumor Transplantation in Preimmunized Animals.- III. Adoptive Transfer of Transplantation Immunity.- D. Immunological Changes in Drug-Resistant Tumor Sublines Defined by Antibodies.- I. Changes in Tumor Antigenicity Defined by Antisera.- II. Changes in Tumor Antigenicity Defined by Monoclonal Antibody.- E. Cellular Immune Responses Against Drug-Resistant Tumor Sublines.- I. Antibody-Forming Cell Responses.- II. Cell-Mediated Cytotoxic Responses.- F. Other Immunobiological Characteristics and Possible Mechanisms of Immunological Changes.- G. Conclusions.- References.- 5 The Molecular Basis of Genetically Acquired Resistance to Purine Analogues in Cultured Mammalian Cells.- A. Introduction.- B. The HPRT Enzyme.- C. Biochemical Basis of Drug Resistance.- D. Drug Resistance as a Consequence of Mutation Within the HPRT Gene.- I. Phenotypic Variation Resulting from Non-mutational Events.- II. Evidence that Drug Resistance Results from Mutation Within the HPRT Gene.- III. Molecular Analysis of the HPRT Gene.- E. Perspectives.- References.- Section III: Cellular Aspects.- 6 Cell Cycle Perturbation Effects.- A. Introduction.- I. General.- II. Proliferating and Quiescent Cells.- III. Age-Dependent Response.- IV. Cell Synchronization.- V. Cell Cycle Perturbation.- VI. In Vitro Systems.- VII. Cell Death.- VIII. Cell Cycle Traverse Rate-Dependent Lethality.- B. Materials and Methods.- C. Results.- I. Proliferating Versus Nonproliferating Cells.- II. Age-Dependent Survival Response.- III. Cell Cycle Perturbation.- 1. Asynchronous Cell Populations.- 2. Synchronized Cells.- IV. Protection of Cell Kill by Inhibition of Cell Cycle Traverse.- D. Discussion.- References.- 7 Tumour Resistance and the Phenomenon of Inflammatory-Cell Infiltration.- A. Introduction.- I. Heterogeneity of Tumour Cells.- II. Intratumour Lymphoreticular Cells: Biological Implications.- III. Methodological Approaches.- B. Characterization of Intratumour Host-Cells.- I. Total Host-Cell Component.- II. Criteria for the Identification of Leucocyte Populations and Subpopulations.- C. Intratumour Leucocytes of Experimental and Human Neoplasms: Descriptive Studies.- I. Preliminary Considerations.- II. Nature of Cells Infiltrating Experimental Neoplasms: Biological Correlates.- III. Nature of Cells Infiltrating Human Neoplasms: Clinicopathological Correlates.- IV. Factors Which Determine Leucocyte Infiltration of Tumours.- D. Effector Functions of Intratumour Leucocytes: Experimental Neoplasms.- I. Systemic Effector Mechanisms.- II. Macrophage Function.- III. T-Cell Function.- IV. Natural Killer Function.- V. Antibody-Dependent Cellular Cytotoxicity.- E. Effector Functions of Intratumour Leucocytes: Human Neoplasms.- I. Macrophage Function.- II. T-Cell Function.- III. Natural Killer Function.- F. Limitations of In Vitro Functional Data.- G. Implications for Therapy.- References.- 8 Flow Cytometric Methods for Studying Enzyme Activity in Populations of Individual Cells.- A. Introduction.- B. Principles of Flow Cytometry.- C. Enzyme Measurements Using Light Absorption.- D. Enzyme Measurements Using Fluorogenic Substrates.- I. Assays with Single Substrates.- II. Assays Using Two Substrates Simultaneously.- E. Conclusions.- References.- 9 Chromosome Studies.- A. Introduction.- B. Chromosome Constitution and Resistance.- I. Derivation of Drug-Resistant Cells.- II. Resistance to Various Classes of Antitumour Drugs.- 1. Purine Analogues.- 2. Pyrimidine Analogues.- 3. Antifolates.- 4. Alkylating Agents.- 5. Platinum Compounds.- 6. Antibiotics.- 7. Vinca Alkaloids.- C. Resistance to Induced Chromosome Damage.- D. Summary.- References.- 10 Alterations of Drug Transport.- A. Introduction.- B. Mechanism of Drug Transport.- I. Characteristics of Passive Diffusion and Mediated Transport.- II. Kinetics of Membrane Transport.- III. Drug Uptake by Multiple Mechanisms.- IV. Evaluation of Drug Efflux.- C. Antitumor Drug Resistance Due to Defects in Membrane Transport.- I. Alkylating Agents.- 1. Nitrogen Mustard.- 2. Melphalan.- 3. Cyclophosphamide.- 4. Nitrosoureas.- 5. Chlorambucil.- 6. Busulfan.- 7. Procarbazine.- 8. Hexamethylmelamine and Pentamethylmelamine.- II. Antimetabolites.- 1. Methotrexate.- 2. 6-Mercaptopurine and 6-Thioguanine.- 3. Fluorouracil.- 4. Arabinosylcytosine and Arabinosyladenine.- III. Antibiotics.- 1. Actinomycin D.- 2. Daunorubicin and Doxorubicin.- 3. Bleomycin.- 4. Mitomycin C.- IV. Alkaloids.- 1. Vinca Alkaloids.- 2. Colchicine.- V. Hormones.- 1. Glucocorticoids.- 2. Estrogens.- 3. Androgens and Progestins.- D. Future Considerations.- References.- 11 Cell Hybridisation.- A. Introduction.- B. Cell Fusion In Vivo.- I. Occurrence of Multinucleate Cells.- II. Experimental Production of Hybrids In Vivo.- III. Modified Pheno…