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Index 451

Index

A B 9-AC, see 9-Aminocamptothecin Bcl-2, mutation and I Albumin, interactions, poison sensitivity, 83, 92, 159 172–174, 202 BCRP, drug transport, 155, 156, 160 9-Aminocamptothecin (9-AC), Benzo[a]acridine, mechanism and brain tumors, structure, 64, 65 clinical trials, 362 Berberine, mechanism and structure, preclinical studies, 351 64, 65 clinical trials, BLM, mutation and topoisomerase I leukemia, 440 poison sensitivity, 83, 90, 91 phase I trials, 194–196 BMS0250749, mechanism phase II trials and antitumor and structure, 64, 65 activity, 198–201 BN-80915, drug development lessons, 199, potency, 63 202, 203 structure, 64 historical perspective, 194 BN-80927, brain tumor preclinical human xenograft model studies, studies, 352 131, 132 BNP1350, structure, 43 pharmacology, 196–198 Brain tumors, see also specific tumors, preclinical studies, 193 9-aminocamptothecin, structure, 43, 345, 346 clinical trials, 362 Animal models, see Preclinical preclinical studies, 351 models, topoisomerase I drug BN-80927 preclinical studies, 352 evaluation camptothecin preclinical Ara-C, see studies, 351 ATM, classification, 344 epidemiology, 343, 344 activation after DNA damage, 86 , mutation and topoisomerase I clinical trials, 359–362 poison sensitivity, 83, 86, preclinical studies, 349–351 87, 158 karentecin preclinical studies, 351 substrates, 87 prospects for camptothecin ATR, analog therapy, 362, 363 DNA repair pathway, 89, 90, 158 silatecans preclinical studies, 352 mutation and topoisomerase I survival, 344, 345 poison sensitivity, 83 , 451 452 Index

clinical trials, 352–359 toposomerase I alterations, preclinical studies, 347, 348 156, 157 Breast cancer, side effects, 62, 423 rubitecan trials, 217 structure, 40, 64, 345, 346 topotecan therapy, 278, 279 structure-activity relationships, 42, 44 C , rubitecan combination Camptosar, see Irinotecan therapy, 214 Camptothecin (CPT), , albumin interactions, 172–174 irinotecan combination therapy, analog studies, 400, 401, 406, 407, 410, 412 electrophilic analogs, 47, 48 topotecan combination therapy, modifications at position 20, 280–282, 377, 385–388, 436 48, 50, 51 Cervical cancer, rational design, irinotecan trials, 235 A/B-ring design for el- topotecan therapy, 279 evated lactone levels, Chebulagic acid, DNA relaxation 174–177 effects with topoisomerase-I, 46 E-ring design, 177–180 Chordoma, rubitecan trials, 219 vesicle interactions, 176, 177 , brain tumor preclinical studies, 351 irinotecan combination therapy, 233, 397, 400–402, 404, 406 cyclodextrin formulations, 180–182 rubitecan combination therapy, 213 discovery, 153, 207, 301 topotecan combination therapy, E-ring transformations, 42–44, 302 282, 377, 385, 392–394 hydrolysis, 172 Colorectal cancer, leukemia trials, 423 therapy, 335 liposomal formulations, 183–185 irinotecan trials, 231–233 mechanism of action, rubitecan trials, 217, 218 base flipping model, 4, 5 topotecan therapy, 277 covalent intermediate binding, 24 Coralyne, mechanism and structure, 5'-end misalignment model, 62, 44, 45, 64, 65 69–72 Corilagin, DNA relaxation effects intercalation model, 5, 27, 31, 33 with topoisomerase-I, 46 ternary complex formation, 41, 42 CPT, see Camptothecin resistance, CPT-11, see Irinotecan cellular response alterations to CSB, chromatin remodeling, 91 ternary complex formation, Cyclodextrin, drug formulations, 157–160 180–182 clinical specimen analysis, , topotecan 160–162 combination therapy, 383, 436 metabolism and transport, Cytarabine (Ara-C), topotecan 154–156 combination therapy, 283, 431, overview, 44, 153, 154 434–438 Index 453

D Tdp1 role in 3'-end processing, 77–79 , topotecan combina- XRCC1/poly(ADP-ribose) tion therapy, 431 ` DB-67, polymerase/ -polymerase/ cyclodextrin formulations, 180–182 ligase III complex role, 81–84 design, 175 DNA replication, vesicle interactions, 176, 177 inhibition by topoisomerase I DB-202, vesicle interactions, 176 poisons, 73, 75 DE-310, exatecan prodrug, 318, 336 topoisomerase I poison Dihydrocoralyne, mechanism and dependence, 73 structure, 44, 45 DOA4, mutation and topoisomerase DNA damage, I poison sensitivity, 160 lesions as topoisomerase I poisons, , irinotecan combination 6, 69, 72 therapy, 407, 410 nonreversible topoisomerase I DX-8951f, see Exatecan cleavage complex, 73 E repair, see DNA repair, topoisomerase I covalent Ead51C, mutation and complexes topoisomerase I poison DNA-dependent protein kinase, sensitivity, 83 mutation and topoisomerase I Ecteinascidin 743 (ET-743), poison sensitivity, 83, 88 mechanism and structure, 67, 68 DNA ligase III, DNA repair of Endometrial cancer, topotecan topoisomerase I covalent therapy, 279 complexes, 81–84 , topotecan combination DNA polymerase-`, DNA repair therapy, 377 of topoisomerase I covalent E-ring, complexes, 81–84 crystal structure of mechanism, DNA repair, topoisomerase I covalent 27, 31, 36 complexes, drug design, 9.1.1 pathway, 89, 90 hydrolysis profile alteration, ATM-MRE11/RAD50/NBS1 177, 178 repair pathways, 86–88 nonenzymatic activation, 178–180 ATR pathway, 89, 90 transformations, 42–44 chromatin remodeling pathways, 91 Fanconi anemia pathway, Esophageal cancer, irinotecan trials, 233 Ku/DNA-dependent protein ET-743, see Ecteinascidin 743 kinase repair pathway, 88 , p53 pathway, 92 irinotecan combination therapy, RecQ pathway, 90, 91 401, 402 replication-mediated double- topotecan combination therapy, strand breaks, 79, 80 283, 284, 383, 385–387, suicide complex formation, 76, 77 429–431, 434, 435 454 Index

Exatecan (DX-8951f), rubitecan combination therapy, clinical applications, 213, 214 colorectal cancer, 335 topotecan combination therapy, gallbladder cancer, 334, 335 281, 394 leukemia trials, 440 GI147211, see pancreatic cancer, 334 Gilbert’s disease, irinotecan pediatric cancer, 335, 336 toxicity, 245 DE-310 prodrug, 318, 336 Glioblastoma multiforme, rubitecan metabolism, 322, 323 trials, 218 phase I trials, Glioma, antitumor activity, 329, 330 irinotecan trials, 235 dosing, 323, 324, 333, 334 topotecan therapy, 278 maximum tolerated dose, H 327–329 , 324–326, Head and neck cancer, topotecan 330, 332 therapy, 278 toxicity, 326, 327 Histone H2AX, phosphorylation preclinical studies, in DNA damage, 91 antitumor activity, 318–320 Ho-33258, mechanism and structure, pharmacology, 322 65, 67, 68 potency, 318 Ho-33342, mechanism and structure, resistance, 320, 321, 337 65, 67, 68 toxicology, 322, 323 Homocamptothecin, prospects for use, 337 potency, 63 structure, 43, 318, 319 rationale design, 177, 178 structure, 44, 64 F Homosilatecan, structure and rationale Fagaronine, mechanism and structure, design, 177, 178 44–46 hTOP1, see Topoisomerase I , topotecan combination Hycamtin, see Topotecan therapy, 437, 438 7-Hydroxystaurosporine (UCN-01), 5-, irinotecan synergistic killing with combination therapy, 232 , 75 G I Gallbladder cancer, exatecan , topotecan combination therapy, 334, 335 therapy, 383 Gastric cancer, Irinotecan (CPT-11), irinotecan trials, 233 activation, 130, 132, 154, 178, 179, rubitecan trials, 219 229, 237, 238 , analogs for nonenzymatic irinotecan combination therapy, 439 activation, 178–180 Index 455

brain tumors, J clinical trials, 359–362 J-107088, mechanism and structure, preclinical studies, 349–351 64, 65 clinical indications, 127, 128, 209, 230 K clinical trials, Karentecin, brain tumor preclinical cervical cancer, 235 studies, 351 colorectal cancer, 231–233 Ku, DNA repair, 88 esophageal cancer, 233 gastric cancer, 233 L glioma, 235 Leukemia, leukemia, 438–440 9-aminocamptothecin trials, 440 lung cancer, camptothecin analog therapy non-small cell lung cancer, rationale, 422 234, 402–412 camptothecin trials, 423 small cell lung cancer, 234, exatecan trials, 440 235, 394–402 irinotecan trials, 438–440 pancreatic cancer, 234 topotecan therapy, clinical/molecular correlations, combination therapy, 283, 284, 235, 236 429–438 discovery, 231 monotherapy, 275, 276, 423–429 dosing, 230 phase I studies, 423–427 drug–drug interactions, 246 phase II studies, 427–429 formulations, 231 treatment needs and prospects, human xenograft model studies, 132 421, 422, 440–442 interspecies differences in drug Lung cancer, metabolism and disposition, classification and staging, 370 142–144 epidemiology, 369 mass balance and , 244 irinotecan trials, metabolism, 154, 229, 230, 238, non-small cell lung cancer, 234 245, 246 small cell lung cancer, 234, 235 pharmacodynamics, 243, 244 irinotecan trials, pharmacokinetics, 239–243 non-small-cell lung cancer, prospects for use, 250, 251 combination therapy, 404–412 side effects, monotherapy, 403, 404 cholinergic syndrome, 247 small-cell lung cancer, late-onset diarrhea, 247–250 combination therapy, 397–402 miscellaneous toxicity, 250 monotherapy, 234, 394–397 nausea and vomiting, 250 prospects for treatment, 413 overview, 231, 246, 247 rubitecan trials, special patient populations, 245 non-small-cell lung cancer, 220 structure, 40, 64, 303, 345, 346 small-cell lung cancer, 220 transport, 238, 239 survival, 369 456 Index

topotecan trials, NBS1, mutation and topoisomerase I non-small-cell lung cancer, poison sensitivity, 83, 87, 88 combination therapy, 282, NHL, see Non-Hodgkin’s lymphoma 283, 392–394 9.1.1, DNA repair pathway, 89, 90 monotherapy, 277, 389–391 Nitidine, mechanism and structure, small-cell lung cancer, 44, 45, 64, 65 combination therapy, 282, 9-Nitrocamptothecin, see Rubitecan 374–388 Nogalamycin, mechanism of action, 6 comparative study Non-Hodgkin’s lymphoma (NHL), with cyclophosphamide, topotecan therapy, 28 , NSC-314622, mechanism and struc- and , 374 ture, 64, 65 monotherapy, 273–275, NU/ICRF 505, mechanism and 371–374, 378 structure, 67, 69 Lurtotecan, O clinical trials, phase I trials, 304–307 Ovarian cancer, phase II trials, 308, 309 rubitecan trials, 215 liposomal formulations, topotecan trials, 270–273, 280–282 overview, 183, 184 , irinotecan combination phase I trials, 311–313 therapy, 233 preclinical studies, 309, 310 P preclinical studies, 303 prospects for use, 313 p53, structure, 302–304, 345, 346 activation in replication-mediated DNA damage, 84, 92 M mutation and topoisomerase I poison sensitivity, 83 Melanoma, rubitecan trials, 218 , , topotecan combination irinotecan combination therapy, therapy, 431 402, 407, 409, 410, 412 MJ-III-65, mechanism and structure, topotecan combination therapy, 64, 65 280–282, 284, 377, 378, 381, MRP2, drug transport, 155 382, 387, 388, 392–394 MSH2, mutation and topoisomerase Pancreatic cancer, I poison sensitivity, 158 exatecan therapy, 334 Myelodysplasia, irinotecan trials, 234 rubitecan trials, 217 rubitecan trials, 215–217, 220, 221 topotecan therapy, 275, 283 PARP, see Poly(ADP-ribose) N polymerase Pediatric tumors, NB-506, mechanism and structure, exatecan trials, 335, 336 64, 65, 111 topotecan trials, 276 Index 457

5-Phenylterbenzimidazole, Radiation therapy, rubitecan mechanism and structure, 67, 68 combination, 210, 211, 214 Phthalascidin (PT-650), mechanism RecQ helicase, replication-mediated and structure, 67, 68 double-strand break repair, 80, Pnk1, mutation and topoisomerase I 81, 90 poison sensitivity, 158, 159 Rubitecan, PNKP, see Polynucleotide kinase clinical trials, phoasphatase phase I trials, Poly(ADP-ribose) polymerase capecitabine combination (PARP), DNA repair of therapy, 214 topoisomerase I covalent cisplatin combination complexes, 81–84 therapy, 213 Polynucleotide kinase phoasphatase gemcitabine combination (PNKP), role in 3'-end processing therapy, 213, 214 of topoisomerase I covalent monotherapy, 211–213 complexes, 79 phase II trials, Preclinical models, topoisomerase I breast cancer, 217 drug evaluation, chordoma, 219 drug resistance models, 138 colorectal cancer, 217, 218 historical perspective, 128, 129 gastric cancer, 219 human xenograft models, 130–136 glioblastoma multiforme, 218 interspecies difference melanoma, 218 considerations, myelodysplasia, 217 and disposition, non-small-cell lung cancer, 220 142–144 ovarian cancer, 215 pancreatic cancer, 215–217 protein binding, 144 small-cell lung cancer, 220 prospects, 145, 146 soft tissue sarcoma, 218, 219 rodent tumor models, 129, 130 urothelial tract cancer, 220 schedule-dependent antitumor phase III trials of pancreatic activity in animal models, cancer, 220, 221 133, 138 liposomal formulations, 185 toxicity evaluation, pharmacokinetics, 221–224 gastrointestinal toxicity, preclinical studies, 208, 210 hamster, 141 prospects for use, 224, 225 mouse, 140 radiation therapy combination, rat, 140, 141 210, 211, 214 hematopoietic toxicity, 138, 139 structure, 208, 210, 345, 346 PT-650, see Phthalascidin synthesis, 208 R S RAD9, mutation and topoisomerase Silatecans, brain tumor preclinical I poison sensitivity, 158 studies, 352 458 Index

SN-38 ternary enzyme–DNA–drug metabolism, 154, 229, 230, 238, 245 complex, 24, 26, 27, 29 pharmacodynamics, 243, 244 persistence during DNA pharmacokinetics, 239–243 replication, 39 prodrug development, 179, 180 repair, see DNA repair structure, 40, 64 reversibility, 72, 73 transport, 238, 239 SUMO-1 modification, 10, 11 vesicle interactions, 176 ubiquitination and enzyme Soft tissue sarcoma, rubitecan trials, degradation, 8–10 DNA minor groove ligand poi- 218, 219 soning mechanism, 71, 72 SR proteins, phosphorylation by functions, topoisomerase I, 54 nonhomologous recombination, SUMO-1, 52, 53 camptothecin toxicity role, 11, 160 overview, 23 sumoylation comparison SR protein phosphorylation, 54 with ubiquitination, 86 inhibition strategies, 46, 47 topoisomerase I cleavable mutations and drug resistance, complex modification, 10, 156, 157, 160 11, 86, 160 poisons, camptothecin, 4, 5, 63–65 T DNA lesions, 6, 69, 72 Tdp1, role in 3'-end processing noncamptothecins, 5, 6, 44–46, of topoisomerase I covalent 65–69 complexes, 77–79 site-directed mutagenesis Terbenzimidazole, mechanism studies, 51 and structure, 67, 68 tumor overexpression, 172 TOP-I, see Topoisomerase I yeast mutants, see Yeast Topoisomerase I, topoisomerase I mutants catalytic reaction, 23, 24, 109, 110 Topotecan, administration, 263, 264, 266, 267 cleavable complex, brain tumors, cellular processing, 7 clinical trials, 352–359 covalent modification, 7, 8 preclinical studies, 347, 348 crystallography studies, clinical indications and trials, DNA relaxation effects, 31, combination therapy, 33, 34 hematological malignancies, drug binding pocket model, 283, 284, 429–438 31, 32 non-small-cell lung cancer, E-ring, 27, 31, 36 282, 283, 392–394 hydrogen bonds with drug, ovarian cancer, 280–282 29–31 rationale, 279, 280 open-versus-closed drug small-cell lung cancer, 282, structure, 27, 29, 31, 36 374–388 Index 459

high-dose and Transcription, topoisomerase I stem cell transplantation, poison effects, 75, 76 283, 284 Transcription factors, role monotherapy, in topoisomerase I breast cancer, 278, 279 downregulation cervical cancer, 279 by camptothecin, 9 colorectal cancer, 277 TRF genes, expression and endometrial cancer, 279 topoisomerase I inhibitor toxicity, glioma, 278 54, 55 head and neck cancer, 278 leukemia, 275, 276, 423–429 U myelodysplasia, 275 Ubiquitination, non-small-cell lung cancer, steps, 85 277, 389–391 sumoylation comparison, 86 ovarian cancer, 270–273 topoisomerase I cleavable pediatric tumors, 276 complex enzyme degradation, small-cell lung cancer, 8–10, 85, 159, 160 273–275, 371–374, 378 UCN-01, see 7- overview, 128, 209, 263 Hydroxystaurosporine crystallography studies of mechanism, V DNA relaxation effects, 31, 33, 34 , topotecan combination drug binding pocket model, therapy, 283 31, 32 E-ring, 27, 31, 36 W hydrogen bonds with drug, WRN, mutation and topoisomerase I 29–31 poison sensitivity, 83, 90, 91, 158 open-versus-closed drug structure, 27, 29, 31, 36 X ternary enzyme–DNA–drug X-ray crystallography, complex, 24, 26, 27, 29 camptothecin binding in drug–drug interactions, 269 topisomerase I active site, 48 mechanism of action, 264 topotecan studies, pharmacokinetics, DNA relaxation effects, 31, 33, 34 absorption, 265 drug binding pocket model, 31, 32 distribution, 265 E-ring, 27, 31, 36 elimination, 265, 266 hydrogen bonds with drug, metabolism, 265, 266 29–31 pharmacodynamics, 268 open-versus-closed drug prospects for use, 285, 286 resistance mechanisms, 270 structure, 27, 29, 31, 36 structure, 40, 64, 264, 303, 345, 346 ternary enzyme–DNA–drug toxicity, 268, 269 complex, 24, 26, 27, 29 460 Index

XRCC1, advantages as model system, 111 DNA repair of topoisomerase I camptothecin resistance covalent complexes, 81–84 of deletion mutants, 112 mutation and topoisomerase I cellular responses to poisons, poison sensitivity, 83 116–120 XRCC2, mutation and derivation, 112 topoisomerase I poison drug uptake, 112, 117, 118 sensitivity, 83 site-directed mutants and camptothecin sensitivity, Y 113–116 Yeast topoisomerase I mutants, viability, 111