Mechanisms of Drug Resistance in Neoplastic Cells (eBook)

Front Cover 1
Mechanisms of Drug Resistance in Neoplastic Cells 4
Copyright Page 5
Table of Contents 6
Contributors 14
Editor's Foreword 22
Foreword 24
Preface 26
PART 1: General Considerations of Drug Resistance 28
Chapter 1. Colon Cancer as a Model for Resistance to Antineoplastic Drugs 30
I. Introduction 30
II. Types of Resistance: Intrinsic and Acquired 31
III. Clinical Resistance of Colon Cancer 32
IV. Behavior of Colon Cancer Cells in the Human Tumor Stem-Cell Assay 32
V. Effects of Radiation and Oxygen Radicals on Colon Carcinoma Cells 34
VI. A Model of Colon Cancer Resistance 36
VII. Circumventing Resistance 37
Acknowledgments 38
References 38
Chapter 2. Mathematical Modeling of Drug Resistance 40
I. Introduction 40
II. A Model for the Appearance of a Single Resistant Phenotype 41
III. Implications of a Stem-Cell Model of Tumor Growth for the Acquisition of Drug Resistance 45
IV. Effect of Variability in the Mean Value of the Mutation Rate in the System 49
V. Effect of Treatment Sequencingand the Question of Dose intensity 50
VI. Partial Resistance 53
VII. Summary and Conclusions 53
References 54
Chapter 3. On the Mechanism of Induced Gene Amplification in Mammalian Cells 56
I. Introduction 56
II. Enhancement of the Frequ 57
III. Overreplication of DNA following Inhibition of DNA Synthesis 60
IV. On the Mechanism of Overreplication of DNA 62
V. Overreplication–Recombination and the Generation of Amplifications and Chromosomal Aberrations–Mutations 63
VI. Consequences for Tumor Progressionand Chemotherapy Resistance 64
Acknowledgments 65
References 66
Chapter 4. Cellular Concomitants of Multidrug Resistance 68
I. Introduction 69
II. Plasma Membrane Glycoprotein(gp150-180/P-Glycoprotein) 72
III. Chromosomal Organizationof Amplified MDRA Genes 78
IV. Low-Molecular-Weight Cytosolic Protein (Sorcin/V19) 84
V. EGF Receptor 88
VI. Summary and Overview 90
Acknowledgments 91
References 91
Chapter 5. Resistance to Alkylating Agents:Basic Studies and Therapeutic Implications 96
I. Introduction 96
II. Development of Resistanceto Alkylating Agents 97
III. High-Dose Effect of Alkylating Agents—Experimental Model 99
IV. Cross-Resistance among Alkylating Agents 100
V. Resistance Mechanisms—Heterogeneity 103
VI. Other Studies of Resistance Mechanisms 104
VIII. Multilog Cell Kill for Alkylating Agents and Nonalkylating Agents against Sensitive Tumors 106
IX. Cross-Resistance among Alkylating Agents as Determined from Multilog Kill Analyses 108
X. Multilog Survival Analysis—Duration of Drug Exposure 109
XI. Synergism 109
XII. Conclusions 110
References 111
Chapter 6. Phosphoprotein and ProteinKinase C Changes in Human Multidrug-Resistant Cancer Cells 114
I. Introduction 115
II. Human Breast Cancer Lines 115
III. Human Small-Cell Lung Cancer Lines 119
IV. Protein Kinase C 120
V. Conclusions 122
References 122
PART II: Enzymatic Basisof Drug Resistance 124
Chapter 7. Novel Drugs That Affect Glutathione Metabolism 126
I. Introduction 126
II. Summary of Glutathione Metabolismand Transport 127
III. Decrease of Cellular Glutathione by Inhibitionof .-Glutamylcysteine Synthetase 129
IV. Methods for Increasing CellularLevels of Glutathione 135
V. Prospects for More Effective Agentsand for the Development of Other Approachesto the Modulation of Glutathione Metabolism 146
References 149
Chapter 8. Regulation of Genes Encoding Drug-Metabolizing Enzymes in Normal and Preneoplastic Tissues 154
I. Introduction 155
II. Rat Liver Glutathione S-Transferase 155
III. Analysis of a Rat Liver GlutathioneS-Transferase Ya Structural Gene 158
IV. Regulation of Rat Liver GlutathioneS-Transferase mRNAs by Xenobiotics 159
V. Expression of Glutathione S-Transferases,Epoxide Hydrolase, and Quinone Reductase Genes during Chemical Carcinogenesis 162
VI. Conclusions 164
Acknowledgments 165
References 165
Chapter 9. Glutathione S-Transferasesand Anticancer Drug Resistance 168
I. Introduction 168
II. The Resistant Phenotype in Walker 256 Rat Breast Carcinoma Cells 170
III. Drug Resistance and an Altered GlutathioneS-Transferase Phenotype in Cell Culture 172
IV. Subcellular Compartmentalization of Glutathione S-Transferases 178
V. Glutathione S-Transferases in Human Biopsies 179
VI. Discussion 183
References 184
Chapter 10. Cellular Resistanceto Cyclophosphamide 188
I. Cyclophosphamide Metabolism 188
II. Tumor-Cell Resistance Dueto Aldehyde Dehydrogenase 189
III. Normal Tissue Resistance Dueto Aldehyde Dehydrogenase 194
IV. Tumor-Cell Resistance Dueto Glutathione S-Transferase 195
V. Other Potential Mechanisms of Resistance to Cyclophosphamide 196
References 197
Chapter 11. Preclinical and Clinical Experiences with Drug Combinations Designed to Inhibit DNA Repair in Resistan tHuman Tumor Cells 200
I. Introduction 200
II. Materials and Methods 202
III. Results 203
IV. Discussion 207
Acknowledgments 209
References 209
Chapter 12. Modification of the Cytotoxicity of DNA-Directed Chemotherapeutic Agents by Polyamine Depletion 210
I. Introduction 211
II. Polyamine Biosynthesis and Inhibitionof Pathways 211
III. Binding of Polyamines to Nucleic Acids 212
IV. Effect of Polyamine Depletionon Nitrosourea Cytotoxicity 213
V. Effects of Polyamine Depletionon c/s-Platinum Cytotoxicity 217
VI. Effects of Polyamine Depletionon Other Cytotoxic Agents 218
VII. Other Effects 218
Acknowledgments 219
References 219
PART III: Multidrug Resistance 222
Chapter 13. Multidrug Resistanceand P-Glycoprotein Expression 224
I. Introduction 224
II. Overexpression of P-Glycoprotein 225
III. P-Glycoprotein Gene Amplification 226
IV. P-Glycoprotein Gene Transfection 227
V. Structure of P-Glycoprotein 227
VI. Does P-Glycoprotein Cause Multidrug Resistance? 231
Acknowledgments 233
References 233
Chapter 14. Different Mechanisms of Multiple Drug Resistance in Two Human Leukemic Cell Lines 238
I. Introduction 239
II. Results and Discussion 239
III. Summary and Conclusions 246
Acknowledgments 247
References 247
Chapter 15. Multidrug Resistancein the Mouse Macrophage-Like Cell Line J774.2 250
I. Introduction 250
II. Isolation of Drug-Resistant Cell Lines 251
III. Characterization of Resistant-Specific Proteins 255
IV. Gene Amplification 262
V. Summary 266
Acknowledgment 267
References 267
Chapter 16. Expression, Amplification, and Transfer of DNA Sequences Associated with Multidrug Resistance 270
I. The Biological Problem of Multidrug Resistance 271
II. Development of a Genetic System for the Studyof Multidrug Resistance in Human KB Cells 271
III. Drug Binding by P-Glycoprotein 277
IV. Clinical Implications: Expression of the mdrl Gene Product in Normal Tissues and Tumors 281
Acknowledgments 282
References 282
Chapter 17. Cytogenetic and Molecular Biologic Alterations Associated with Anthracycline Resistance 286
I. Introduction 287
II. Properties of Resistant Cell Lines 287
III. Cytogenetic Alterations Associated with the Acquisition of Anthracycline Resistance 289
IV. Molecular Alterations Associatedwith Anthracycline Resistance 298
V. Conclusions 301
Acknowledgments 302
References 302
Chapter 18. Roles of DNA Topoisomerases in Drug Cytotoxicity and Drug Resistance 304
I. DNA Topoisomerase II as a Therapeutic Targetin Cancer Chemotherapy 305
II. DNA Topoisomerase I as a Possible Therapeutic Target in Cancer Chemotherapy 311
Acknowledgment 312
References 312
PART IV: Circumvention of Resistance 314
Chapter 19. Manipulation of Cellular Thiols to Influence Drug Resistance 316
I. Introduction 316
II. Glutathione Levels and Drug Resistance 318
III. Experimental Model Systems of Human Ovarian Cancer 319
IV. GSH Metabolism and Effects of BSO in Vitroand in Vivo 322
V. DNA Repair in Drug-Resistant Cells 328
VI. Discussion 330
References 331
Chapter 20. Drug Resistance as a Focus for New Drug Design 334
I. Introduction 334
II. Background 336
III. Implications for Further Drug Development 344
IV. Relevance of Several Antitumor Screening Models for Analog Development 344
V. Summary 352
Acknowledgments 352
References 353
Chapter 21. Manipulation of Drug Accumulation: Mechanismsto Overcome Resistance 356
I. Introduction 356
II. Multiple Acquired Drug Resistance (MADR):Patterns of Cross-Resistance Relatedto Decreased Drug Accumulation 357
III. Multiple Intrinsic Drug Resistance (MIDR):Selective Cellular Sensitivity Relatedto Drug Accumulation 361
IV. Circumvention of MADR and MIDR 364
V. Conclusions 367
Acknowledgments 369
References 369
Chapter 22. Manipulation of Antineoplastic Drug Sensitivity and Resistance by DNA Transfection 374
I. Introduction 374
II. Strategies for Circumvention of Drug Resistance with Gene-Insertion Methodologies 376
III. Intrinsic Construct and Target Requirementsfor Successful DNA Transfections 376
IV. Gene Insertion Methodologies 378
V. Therapeutic Perspectives for Gene Therapyin Circumventing Drug Resistance 393
Acknowledgments 394
References 394
Chapter 23. Potential Use of Monoclonal Antibody—Drug Conjugatesto Prevent Drug Resistance 398
Acknowledgments 408
References 408
Index 412