Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma.
CPT-11, a semi-synthetic derivative of camptothecin, was investigated for its activity in panels of 15 human ovarian-cancer lines and 10 human soft-tissue sarcoma lines grown s.c. in nude mice. Various factors were analyzed that may be of influence on the extent of tumor-growth inhibition induced by CPT-11. At equitoxic doses, CPT-11 was more effective in the daily x5 schedule than the weekly x2 schedule, although a 2-fold higher dose was administered in the weekly x2 schedule. Since i.p. and i.v. injections were similarly effective, the selected treatment schedule was 20 mg/kg i.p. daily x5, starting when tumors measured approximately 150 mm3. Growth inhibition of > or = 75% was obtained in 8/15 human ovarian-cancer lines and in 6/10 human soft-tissue sarcoma lines. A weak correlation was found between topoisomerase-I mRNA in xenograft tissues and sensitivity to CPT-11. Relative topoisomerase-I expression was highest in MRI-H-207 and WLS-160 xenografts, in which CPT-11 was able to induce cures of all tumors. The high efficacy in the 2 panels of human tumor lines suggests over-prediction of its potential clinical activity in these tumor types. The difference in efficacy of CPT-11 between species may be related to the metabolism of the drug, since CPT-11 is converted more efficiently into SN-38 in mice. In addition, mice may be less sensitive to SN-38-induced side-effects. On the basis of the preclinical data, frequent administration of lower doses of CPT-11 should be considered in order to increase response rates in the clinic.
Jansen
W J
WJ
Department of Medical Oncology, Academic Hospital, Vrije Universiteit, Amsterdam, The Netherlands.
Kolfschoten
G M
GM
Erkelens
C A
CA
Van Ark-Otte
J
J
Pinedo
H M
HM
Boven
E
E
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin