EFFICACY OF SYSTEMIC ADMINISTRATION OF IRINOTECAN AGAINST NEUROBLASTOMA XENOGRAFTS

The efficacy of the topoisomerase I inhibitor 7-ethyl-10(4-[1-piperidi no]- 1-piperidino)-carbonyloxy-camptothecin (irinotecan, CPT-11) has b een examined against a panel of six independently derived neuroblastom a xenografts, Intensive courses of therapy, where irinotecan was admin istered i.v. daily 5 days per week for two consecutive weeks [(dx5)2; defined as 1 cycle], were compared to more protracted low-dose schedul es where cycles were repeated every 21 days for a total of three cours es (abbreviated [(dx5)2]3}. When administered (dx5)2 for a single cycl e, the maximum tolerated daily dose was 40 mg/kg, Irinotecan induced a high frequency of complete regressions (CRs) in four of the six lines examined; however, most tumors achieving CR regrew during the period of observation (12 weeks). Furthermore, there was no advantage in high -dose regimens as compared to low dose (10 mg/kg) on the same schedule , Protracted schedules of administration, where three courses of thera py were given at 21-day intervals {[(dx5)2]3} i.v. were examined at 10 and 5 mg/kg/dose, Even at the lower dose level, irinotecan caused 100 % CR in all tumor lines that were maintained at 12 weeks, To determine the minimum dose levels required to induce objective regressions of n euroblastoma xenografts, decreasing doses were examined using the [(dx 5)2]3 i.v. schedule. At 2.5 mg/kg/dose, >90% of NB-1643, NB-1691, NB-1 382.2, and NB-EB xenografts demonstrated CR, whereas at 1.25 mg/kg/dos e, all six tumor lines evaluated demonstrated objective regressions (g reater than or equal to 50% volume reduction), with a high frequency o f CRs in four tumor lines, The 10-hydroxy-7 ethyl CPT lactone single-d ay systemic exposure measured with the minimum dose (2.5 mg/kg) associ ated with complete response was 198, 257, and 228 ng h/ml for mice bea ring NB-1643, NB-1691, and NB-EB tumors, respectively, These results i ndicate that childhood neuroblastoma xenografts are highly sensitive t o irinotecan given by parenteral administration, and that efficacy is schedule dependent.