Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against human tumor xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin.
The efficacy of the topoisomerase I inhibitor CPT-11 [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxycamptothec in] has been evaluated against a panel of human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas representing intrinsically chemorefractory malignancies, six lines derived from childhood rhabdomyosarcoma (three embryonal and three alveolar) representing a chemoresponsive histiotype, and sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine, melphalan, and the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan). CPT-11 was given by i.v. administration daily for 5 days each week for 2 weeks (one cycle of therapy) or on the same schedule with cycles repeated every 21 days. The maximum tolerated dose for a single cycle of treatment was 40 mg/kg/dose, and for 3 cycles the maximum tolerated dose was 10 mg/kg/dose. Treatment was started against advanced tumors. Against colon adenocarcinomas CPT-11 administered for one cycle at the maximum tolerated dose caused complete or partial regression (> or = 50% reduction in tumor volume) in 5 of 8 lines. One cycle of CPT-11 therapy caused significant inhibition of tumor growth, without 50% regression, in 2 of 3 other colon adenocarcinomas. Rhabdomyosarcoma xenografts derived from untreated patients were highly responsive to CPT-11, which caused complete regression in 5 of 6 lines even at 20 or 10 mg/kg/dose. CPT-11 retained complete activity against rhabdomyosarcomas selected for resistance to vincristine and caused complete regressions in a line selected for resistance to melphalan that was also completely cross-resistant to topotecan. Of note was the observation that CPT-11 was as active against two xenografts selected for primary resistance to topotecan as it was against the respective parental tumors. Preliminary data indicate that CPT-11, like the topoisomerase I inhibitor topotecan, may have increased therapeutic efficacy when administered at a low dose for protracted periods (3 cycles). A comparison of the efficacy of CPT-11 with topotecan is presented.
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
P J
PJ
Houghton
P J
PJ
Cheshire
J C
JC
Hallman
M C
MC
Bissery
A
A
Mathieu-Boué
J A
JA
Houghton
D000293:Adolescent; D000328:Adult; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D019772:Topotecan; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D000077146:Irinotecan; D019772:Topotecan; D008558:Melphalan; D002166:Camptothecin