Antitumor Drug Resistance by N.K. AhmedAntitumor Drug Resistance by N.K. Ahmed

Antitumor Drug Resistance

byN.K. Ahmed, B. Barlogie, W.t. Beck

Paperback | December 7, 2011

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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.
Title:Antitumor Drug ResistanceFormat:PaperbackDimensions:738 pages, 24.4 × 17 × 0.07 inPublished:December 7, 2011Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:3642694926

ISBN - 13:9783642694929

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Table of Contents

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 Phenotypes of Hybrids Induced In Vivo.- C. Use of Drug Resistance for the Selection of Hybrid Clones In Vitro.- D. Expression of Drug Resistance in Hybrid Cells.- I. Dominance and Complementation.- II. Gene Dosage and Functional Hemizygosity.- III. Multifunctional Enzymes.- IV. Steroid Resistance and Enzymic Induction by Hormones.- V. Segregation of Resistance.- VI. Gene Activation.- E. Radiation Responses of Hybrid Cells.- I. Sensitivity to Ionising Radiation and Ultraviolet Light.- II. Rescue of Genes from Lethally Irradiated Cells.- F. Conclusions: Possible Therapeutic Implications of Cell Hybridisation.- References.- Section IV: Modification of Tumor Biochemistry.- 12 Drug Resistance and DNA Repair.- A. Introduction.- B. Mechanisms of DNA Repair.- I. Excision Repair.- 1. Base Modification.- 2. Enzymatic Excision of Base Damage.- 3. Repair of Base Damage.- 4. Nucleotide Excision and Repair.- 5. Influence of Chromatin Structure on DNA Excision Repair.- II. DNA Synthesis on a Template Containing Unexcised DNA Lesions.- C. The Relationship Between DNA Repair and Cellular Sensitivity.- I. Alkylating Agents.- II. Platinum Compounds.- III. Mitomycin C.- IV. Bleomycin.- D. Cell-Cycle Perturbations and Their Possible Relationships to DNA Repair.- E. Attempts to Develop Resistance to DNA-Damaging Drugs in Cultured Cell Lines In Vitro.- F. Conclusions.- References.- 13 Cyclic AMP and Prostaglandins.- A. Cyclic AMP.- I. Cyclic AMP and Neoplasia.- II. Tumour Growth Inhibition by Cyclic AMP and Derivatives.- III. Role of Cyclic AMP in Regression of Hormone-Dependent Mammary Tumours.- IV. Role of Cyclic AMP in Growth Inhibition by the Antitumour Alkylating Agents.- 1. Effect on Cyclic AMP Phosphodiesterase.- 2. Effect on Specific Cyclic-AMP-Binding Proteins.- 3. Alterations in Protein Kinase Activity.- 4. Possible Role of Cyclic AMP in the Cytotoxic Action of Alkylating Agents.- V. Effect of Other Antitumour Agents on the Cyclic Nucleotide System.- B. Prostaglandins.- C. Conclusion.- References.- 14 Properties of Mitochondria.- A. Introduction.- B. Damage of Mitochondrial Membranes by Alkylating Agents.- C. The Structure and Functions of Energy-Coupling Complexes in Mitochondria.- D. Search for Correlations Between Cell Sensitivity or Resistance to Alkylating Agents and Functional State of Mitochondrial Membranes.- References.- 15 Mechanism of "Resistance" Towards Specific Drug Groups.- A. Mechanisms of Alkylation.- B. Mechanisms of Cytotoxicity and Antitumour Action.- C. Selectivity of Antitumour Action of the Alkylating Agents.- D. Patterns of Resistance.- E. Mechanisms of Resistance.- I. Resistance Through Decreased Cellular Uptake.- II. Resistance by Inhibition of the Activation of Prodrugs.- III. Resistance by Deactivation of Reactive Alkylating Agents.- IV. Resistance by Interaction with Non-essential Nucleophiles.- F. Conclusions.- References.- 16 Nitrosoureas.- A. Pharmacology.- B. Mechanisms of Drug Resistance.- C. Significance of Molecular Considerations.- D. Monoadducts and Cross-Linking.- E. Interference with the DNA Repair Process.- F. Subnucleosomal Nitrosourea Binding.- G. Effects on Pyridine Nucleotides.- H. Modulation of Drug Effect with Steroids and Other Transcriptional Modifiers.- J. Overcoming Resistance to Alkylating Agents with Nitrosoureas.- K. Clinical Therapeutic Activity.- L. Conclusions.- References.- Section V: Antimetabolites.- 17 Antipurines.- A. Introduction.- B. 8-Azaguanine.- I. Metabolism and Mechanism of Action.- II. Resistance.- C. 6-Mercaptopurine and 6-Thioguanine.- I. Metabolism and Mechanism of Action.- II. Resistance.- D. 6-Methylthioinosine.- I. Metabolism and Mechanism of Action.- II. Resistance.- E. 9-?-D-Arabinofuranosyladenine.- I. Metabolism and Mechanism of Action.- II. Resistance.- F. Adenine and Adenosine Antipurines.- I. Metabolism.- II. Resistance.- G. Circumvention of Resistance.- I. Derivatives Metabolized by Alternative Routes.- II. Potentiation by a Second Agent.- III. Protected Slow-Release Depot Derivatives.- IV. Coadministration of Inhibitors of Degradative Enzymes.- V. Molecular Alteration to Prevent Catabolism but not Anabolism.- VI. Phosphorylated "Prodrug" Derivatives of Antipurine Nucleotides.- H. Conclusion.- References.- 18 Ribofuranose-containing Analogues of Uridine and Cytidine.- A. Introduction.- B. 6-Azauridine.- I. Another Mechanism for Resistance to 6-Azauridine.- C. 5-Azacytidine.- D. Pseudoisocytidine.- E. 3-Deazauridine.- F. Concluding Statement.- References.- 19 5-Halogenated Pyrimidines and Their Nucleosides.- A. Introduction.- B. Metabolism and Mechanism of Action.- C. Development and Stability.- D. Transport.- E. Decreased Lethal Synthesis.- I. Thymidine Kinase.- II. Uridine Phosphorylase; Uridine Kinase.- III. Orotate Phosphoribosyltransferase; Orotidine-5?-Monophosphate Decarboxylase.- F. Changes in Enzyme Characteristics.- I. Altered (Mutated) Enzymes.- II. Increased Enzyme Activities.- G. Cross-Resistance and Collateral Sensitivity.- H. Tolerance.- J. Natural Resistance.- I. Formation of Nucleotides.- II. Formation of 5-Fluoro-2?-Deoxyuridylate.- III. Accumulation of 2?-Deoxyuridylate.- IV. Concentration of N5N10-Methylenetetrahydrofolate.- V. Enzyme Activities.- VI. Catabolism.- K. Overcoming Resistance.- I. Metabolic Modulation.- 1. Naturally Occurring Pyrimidine Metabolites.- 2. Purines and Purine Analogues.- 3. Methotrexate.- 4. Inhibitors of Pyrimidine Biosynthesis de Novo.- II. Congener Synthesis.- 1. Metabolic Activation.- 2. Decreased Phosphorolytic Cleavage.- 3. Latentiation.- 4. Increased Uptake.- L. Conclusions.- References.- 20 Resistance to Amino Acid Analogs.- A. Definitions.- B. Natural Resistance.- C. Acquired and Cross-Resistance.- I. Glutamine Antagonists.- 1. Biochemistry.- 2. Resistance.- II. Aspartic Acid Antagonists.- 1. Biochemistry.- 2. Resistance.- III. Tyrosine Antagonists.- 1. Biochemistry.- 2. Resistance.- IV. Asparagine Antagonists.- 1. Biochemistry.- 2. Resistance.- V. General Amino Acid Antagonists.- 1. Biochemistry.- 2. Resistance.- D. Summary.- References.- 21 Alkaloids.- A. Introduction.- B. Cellular Pharmacology and Biochemistry of the Vinca and Colchicum Alkaloids.- I. Mechanisms of Alkaloid Accumulation by Cells.- II. Effects of Alkaloids on Cellular Functions.- 1. Membrane Transport.- 2. Other Membrane-Related Actions.- 3. Cytotoxic Lesions.- C. Manifestations of Resistance to the Alkaloids.- I. Resistance and Cross-Resistance Characteristics of Alkaloid-Insensitive Cells.- II. Pharmacological Bases of Alkaloid Resistance.- 1. Decreased Uptake of Drug.- 2. Diminished Retention of Drug.- 3. Role of Calcium.- III. Biochemical Alterations Associated with Alkaloid Resistance.- 1. Membrane Alterations.- 2. Cytoplasmic Alterations.- 3. Relationship Between Biochemical Changes and Alkaloid Resistance.- IV. Genetics of Alkaloid Resistance.- D. Summary and Future Considerations.- References.- Section VI: Antifolates.- 22 Folate Antagonists.- A. Introduction.- B. Intrinsic or Natural Resistance to Methotrexate and Other Folate Antagonists.- C. Acquired Resistance to Folate Antagonists.- I. Gene Amplification and Elevation of Dihydrofolate Reductase.- 1. Organization of the Dihydrofolate Reductase Gene.- 2. Gene Amplification and Resistance to Other Drugs.- II. Impaired Transport as a Mechanism of Resistance to Methotrexate.- III. Altered Dihydrofolate Reductase as a Mechanism of Methotrexate Resistance.- D. Collateral Sensitivity Between Methotrexate-Resistant Cells and Other Agents.- E. Overcoming Resistance to Folate Antagonists.- I. Agents Promoting Methotrexate Transport into Resistant Cells or Tumors.- II. Effects of Dihydrofolate Reductase or Thymidylate Synthetase Inhibitors on Methotrexate-Resistant Cells.- III. Methotrexate-Resistant Cells with an Altered Dihydrofolate Reductase as a Target for Inhibitors.- F. Clinical Studies.- References.- 23 Steroids.- A. Introduction.- I. Structure.- II. Mechanism of Action of Steroid Hormones.- B. Possible Mechanisms of Steroid Resistance.- C. S49 Lymphoma and WEHI-7 Thymoma Murine Cell Lines.- D. The PI798 Mouse Lymphosarcoma.- E. Human Leukemia.- F. Breast Cancer.- I. Estrogen Receptors.- II. Estrogen and Progesterone Receptors.- III. Estrogen Resistance.- IV. Estrogen Receptor and Prognosis.- V. Estrogen Receptor and Response to Chemotherapy.- VI. Current and Future Directions in Research.- G. Conclusions.- References.- Section VII: Modification of Resistance.- 24 Collateral Sensitivity and Cross-Resistance.- A. Introduction.- B. Definition of Terms.- C. Incidence of Collateral Sensitivity and Cross-Resistance in Experimental Animal Tumours.- I. In Vivo Studies.- II. In Vitro Studies.- D. Mechanisms Implicated in Determining Collateral Sensitivity or Cross-Resistance.- E. Establishment, Stability and Reversion of Collateral Sensitivity and Cross-Resistance.- F. Clinical Studies Concerned with the Evaluation of Drug Sensitivity or Cross-Resistance.- G. Implications of Collateral Sensitivity and Cross-Resistance.- H. Concluding Remarks.- References.