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 ×5 schedule than the weekly ×2 schedule, although a 2-fold higher dose was administered in the weekly ×2 schedule. Since i.p. and i.v. injections were similarly effective, the selected treatment schedule was 20 mg/kg i.p. daily ×5, starting when tumors measured approximately 150 mm³. Growth inhibition of ≥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-1 mRNA in xenograft tissues and sensitivity to CPT-11. Relative topoisomerase-1 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.