Efficacy of systemic administration of irinotecan against neuroblastoma xenografts

Joyce Thompson, William C. Zamboni, Pamela J. Cheshire, Lois Lutz, Xiaolong Luo, Yulan Li, Janet A. Houghton, Clinton F. Stewart, Peter J. Houghton

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109 Scopus citations

Abstract

The efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carboxyloxy-camptothecin (irinotecan, CPT-11) has been examined against a panel of six independently derived neuroblastoma xenografts. Intensive courses of therapy, where irinotecan was administered i.v. daily 5 days per week for two consecutive weeks [(dx5)2; defined as 1 cycle], were compared to more protracted low-dose schedules where cycles were repeated every 21 days for a total of three courses {abbreviated [(dx5)2]3}. When administered (dx5)2 for a single cycle, 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 therapy 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 neuroblastoma xenografts, decreasing doses were examined using the [(dx5)2]3 i.v. schedule. At 2.5 mg/kg/dose, >90% of NB-1643, NB-1691, NB-1382.2, and NB-EB xenografts demonstrated CR, whereas at 1.25 mg/kg/dose, all six tumor lines evaluated demonstrated objective regressions (≤50%, volume reduction), with a high frequency of CRs in four tumor lines. The 10-hydroxy-7-ethyl CPT lactone single-day systemic exposure measured with the minimum dose (2.5 mg/kg) associated with complete response was 198, 257, and 228 ng·h/ml for mice bearing NB-1643, NB-1691, and NB-EB tumors, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by parenteral administration, and that efficacy is schedule dependent.

Original languageEnglish (US)
Pages (from-to)423-431
Number of pages9
JournalClinical Cancer Research
Volume3
Issue number3
StatePublished - Apr 23 1997

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Thompson, J., Zamboni, W. C., Cheshire, P. J., Lutz, L., Luo, X., Li, Y., Houghton, J. A., Stewart, C. F., & Houghton, P. J. (1997). Efficacy of systemic administration of irinotecan against neuroblastoma xenografts. Clinical Cancer Research, 3(3), 423-431.