Pharmacology US, Volume 29B. DNA Topoisomerases: Topoisomerase-Targeting Drugs. Advances in

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1 US, Advances in Pharmacology Volume 29B DNA Topoisomerases: Topoisomerase-Targeting Drugs Edited by Leroy F. Liu University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Piscataway, New Jersey Academic Press San Diego New York Boston London Sydney Tokyo Toronto

2 Contents Contributors Preface xvii xiii Clinical Development of Topoisomerase-Interactive Drugs Franco M. Muggia and Howard A. Burris I. "Classical" Topoisomerase Il-Interacting Drugs 2 A. Anthracyclines 2 B. Miscellaneous DNA-Intercalating Drugs 3 C. Nonintercalating Topoisomerase Il-Interacting Drugs 5 II. Other Topoisomerase Il-Interacting Drugs 6 III. Topoisomerase I-Interacting Drugs: Camptothecins 7 IV. Clinical Implications of Topoisomerase-Drug Interactions 21 A. Optimal Dose Scheduling 21 B. Drug Resistance Considerations 22 C. Drug Combinations 22 D. Collateral Sensitivity and Biochemical Modulation 23 V. Conclusion 23 References 23 Topoisomerases in Human Leukemia David Peereboom, Martin Charron, and Scott H. Kaufmann I. Introduction 33 II. Topoisomerase II in Human Leukemia 33 A. Topoisomerase II in Normal Lymphohematopoietic Cells 33 B. Antileukemic Activity of Topoisomerase II-Directed Agents 34 C. Resistance to Topoisomerase II-Directed Agents 36 III. Topoisomerase I in Human Leukemia 41 A. Topoisomerase I in Normal Lymphohematopoietic Cells 41 B. Antileukemic Activity of Topoisomerase I-Directed Agents 41 C. Future Clinical Development of Camptothecin Analogs 42 D. Potential Mechanisms of Resistance 42 IV. Perspective 43 References 45

3 vi Contents Preclinical and Clinical Development of Camptothecins Dan Costin and Milan Potmesil I. Introduction 51 II. Camptothecins in Current Research 54 A. Camptothecin Sodium Salt (NSC ) 54 B. 20(5)-Camptothecin (NSC 94600) 55 C. 9-Aminocamptothecin (NSC ) 55 D. CPT-11 (Irinotecan) 57 E. Topotecah (NSC ) 58 F. Pharmacokinetics and Toxicity 59 G. Combination Therapy 62 H. Drug Resistance 63 III. Conclusion and Perspectives 64 References 66 Mechanisms of Topoisomerase I Inhibition by Anticancer Drugs Yves Pommier, Akihiko Tanizawa, and Kurt W. Kohn I. Topoisomerase I Reaction Mechanisms 73 II. Inducers of Topi-Linked DNA Breaks 76 A. Camptothecins 76 B. Other Inducers 84 III. Suppressors of Topi-Linked DNA Breaks 85 References 85 Drug Resistance Mechanisms of Topoisomerase I Drugs Toshiwo Andoh and Kosuke Okada I. Introduction 93 II. Mutant Cells, CPT-K5, Possess an Altered Form of Topo I Resistant to CPT 95 III. The Mutant Enzyme Possesses Higher Affinity for Recognition Sequences 95 IV. Determination of Mutation Sites of K5 Topo I Responsible for CPT Resistance 96 V. Site-Directed Mutagenesis of Topo I and Expression of Escherichia coli 98 VI. Conclusion 100 References 101

4 Contents Mechanism of Action of Topoisomerase Il-Targeted Antineoplastic Drugs Neil Osheroff, Anita H. Corbett, and Megan J. Robinson I. Introduction 105 II. Topoisomerase II-Targeted Antineoplastic Drugs 106 III. Catalytic Cycle of Topoisomerase II 107 A. Step 1: DNA Binding 108 B. Step 2: Pre-Strand Passage DNA Cleavage/Religation 109 C. Step 3: DNA Strand Passage 110 D. Step 4: Post-Strand Passage DNA Cleavage/Religation 110 E. Step 5: ATP Hydrolysis 110 F. Step 6: Enzyme Turnover 110 IV. Enhancement of Topoisomerase II-Mediated DNA Breakage by Antineoplastic Drugs 111 V. Effects of Antineoplastic Drugs on the Sites of Topoisomerase II- Mediated DNA Breakage 112 VI. Kinetic Pathway by Which Antineoplastic Drugs Enhance DNA Breakage 113 A. Effects of Antineoplastic Drugs on the Pre-Strand Passage DNA Cleavage/Religation Equilibrium 114 B. Effects of Antineoplastic Drugs on the Post-Strand Passage DNA Cleavage/Religation Equilibrium 115 C. Quinolones as a Novel Mechanistic Class of Topoisomerase II- Targeted Drugs 115 VII. Enzyme Interaction Domains for Topoisomerase II-Targeted Drugs 117 VIII. Possible Ramifications of Mechanistic Diversity among Topoisomerase II-Targeted Drugs 118 IX. Perspectives and Conclusions 119 References 119 vii Determinants of Sensitivity to Topoisomerase-Targeting Antitumor Drugs Peter D'Arpa I. Introduction 127 II. Factors Affecting Cleavable Complex Formation 128 A. Intracellular Drug Concentration 128 B. Quantity and Activity of Topoisomerases 128 III. Processing of Cleavable Complexes into Lethal Lesions 131 IV. Responses to Damage Resulting from Cleavable Complexes 132 A. Poly(ADP-ribosyl)ation 133

5 viii Contents B. Cell Cycle Perturbations 134 C. Cell Killing 135 V. Drugs That Inhibit Topoisomerase II without Producing the Cleavable Complex (Type II Drugs) 135 VI. Interactions of Topoisomerases I and II Drugs with Radiations and Other Chemotherapeutics 136 VII. Summary 137 References 137 Resistance of Mammalian Tumor Cells to Inhibitors of DNA Topoisomerase II William T. Beck, Mary K. Danks, Judith S. Wolverton, Mei Chen, Bernd Granzen, Ryungsa Kim, and D. Parker Suttle I. Introduction 145 II. Resistance of Tumor Cells to DNA Topo II Inhibitors: Cellular Pharmacology of the at-mdr Phenotype 146 III. Biochemical Features Associated with the at-mdr Phenotype 148 A. Isozymes of DNA Topo II in Mammalian Cells 148 B. Increased ATP Requirement for Catalytic Activity of Topo II in at-mdr Cells 149 C. Phosphorylation of Topo II in at-mdr Cells 150 D. Role of the Nuclear Matrix in at-mdr 151 IV. Mutations in the Topo Ila Gene and Their Relationship to at-mdr 151 V. Other Features of at-mdr Cells: Pleiotropic Consequences to the Cell of an Altered Topo II 154 A. Altered Plateau Densities and Temperature Sensitivities of at-mdr Cells 154 B. Oncogene Expression in at-mdr Cells 155 C. Relationship between Topo II and Topo I: Alkylator Resistance, Poly(ADP)ribosylation, and DNA Repair in at-mdr Cell Lines 156 D. Distribution of Topo II in at-mdr Cells 157 VI. Possible Mechanisms of at-mdr 157 A. Decreased Topo II Gene Expression 157 B. Increased Strand Religation or Decreased Drug Binding to the Topo II-DNA Complex 158 C. Resistance to "Programmed Cell Death" 159 D. Progression through G 2 Block 160 E. Resistance to Induction of Sister Chromatid Exchanges 160 F. Decreased Poly(ADP-ribose) Polymerase 161

6 Contents ix VII. Questions and Future Directions toward an Understanding of Tumor Cell Resistance to Topo II Inhibitors 161 References 162 A Bacteriophage Model System for Studying Topoisomerase Inhibitors Kenneth N. Kreuzer I. Introduction 171 II. Isolation of w-amsa R Mutants of T4 172 III. A Common Mode of Action for Topoisomerase Inhibitors 173 IV. The Inhibitor Binding Site 174 V. Involvement of Topoisomerase in Mutation Pathways 176 VI. Recombinational Repair of Topoisomerase-DNA Complexes 178 VII. Summary 181 References 182 Drugs Affecting Trypanosome Topoisomerases Theresa A. Shapiro I. Trypanosomes, Their DNA, and Topoisomerases 187 A. Mitochondrial DNA and Topoisomerase Inhibitors 187 B. Nuclear DNA and Topoisomerase Inhibitors 190 II. Antitrypanosomal Drugs 191 III. Discussion 195 References 197 Yeast as a Genetic Model System for Studying Topoisomerase Inhibitors John L. Nitiss I. Introduction 201 II. The Problem of Getting Drugs into Yeast 203 III. Tools for Studying Mechanisms of Drug Resistance in Yeast 204 A. DNA Repair Mutations 204 B. Controlling the Level of Topoisomerase Activity: Effects of Overexpression of TOP2 on Sensitivity to Antitopoisomerase Agents 206 IV. Determining the Targets of Drugs That Inhibit DNA Topoisomerases 206

7 X Contents V. Isolation of Mutations in DNA Topoisomerases That Are Resistant to Antitopoisomerase Agents 209 A. Using Yeast to Identify Camptothecin-Resistant topi Mutants 210 B. Screening and Characterization of Mutants Resistant to Antitopoisomerase II Agents 212 C. Testing Mammalian Topoisomerase Mutations Using Yeast 215 VI. Mechanisms of Cell Killing by Camptothecin and Antitopoisomerase II Agents: The View in Yeast 216 VII. Other Yeast Genes That Play a Role in Drug Sensitivity and Resistance 218 VIII. Future Prospects 220 References 221 DNA Topoisomerase Inhibitors as Antifungal Agents Linus L. Shen and Jennifer M. Fostel I. Introduction 227 A. Role of Topoisomerase Inhibitors in Antimicrobial Chemotherapy 227 B. Fungal Infections and Fungal Topoisomerases 228 II. Identification and Level of Type I and Type II Topoisomerases in Pathogenic Fungi 230 III. Type I DNA Topoisomerase in Candida albicans 233 A. Purification and Chracterization of Topoisomerase I 233 B. Specificity of Different Chemical Agents for the Fungal Topoisomerase I 234 IV. Type II DNA Topoisomerase in Candida albicans 236 A. Purification 236 B. Differential Response of the Mammalian and C. albicans DNA Topoisomerases Us to Inhibitors 238 V. Concluding Remarks 241 References 241 Design of Topoisomerase Inhibitors to Overcome MDRl-Mediated Drug Resistance Allan Y. Chen and Leroy F. Liu I. Introduction 245 II. MDRl-Mediated Drug Resistance in Human Cancers 246 III. Campothecin Overcomes MDRl-Mediated Resistance in Human Carcinoma Cells 247 IV. Some Structural Features for MDR1 Sensitivity 249

8 Contents X1 V. A Model for Overcoming MDRl-Mediated Resistance by Lipophilic Drugs 251 VI. New Topoisomerase Inhibitors That Overcome MDRl-Mediated Resistance 252 VII. Summary 253 References 254 Appendix I: An Introduction to DNA Supercoiling and DNA Topoisomerase-Catalyzed Linking Number Changes of Supercoiled DNA James C. Wang I. The Linking Number 257 II. Single-Strand Passage and Linking Number: Topological Transformation by Type I DNA Topoisomerases 259 III. Double-Strand Passage and Linking Number: Topological Transformation by Type II DNA Topoisomerases 262 IV. Supercoiled DNA 263 V. Free Energy of Supercoiling and the Specific Linking Difference a 265 References 270 Appendix II: Alignment of Primary Sequences of DNA Topoisomerases Paul R. Caron and James C. Wang References 291 Index 299 Contents of Previous Volumes 307