Efficacy of oral irinotecan against neuroblastoma xenografts

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

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

The efficacy of the topoisomerase 1 inhibitor, 7-ethyl-10-(4-[1-piperidino]-1-piperidino) -carbonyloxy-camptothecin (irinotecan, CPT-11), administered by oral gavage has been examined against a panel of six independently derived neuroblastoma xenografts. Irinotecan was administered either daily for 5 days on 12 consecutive weeks {(d x 5)12} or for 5 days on two consecutive weeks repeated every 21 days for 4 cycles {[(d x 5)2]4}. Given on the (d x 5)12 schedule the maximum tolerated dose (MTD) was 50 mg/kg. For intermittent scheduling {[(d x 5)2]4}, the MTD was 75 mg/kg, resulting in the same total dose being administered (3 g/kg) over the period of treatment. At the MTD for the 12 consecutive week schedule there were two of 42 toxicity related deaths, whereas intermittent scheduling at the MTD resulted in none of 42 intermittent schedule {[(d x 5)2]4} was less therapy given (d x 5)12, as at the end of treatment mice weighed 92 ± 4% (SD; n = 6 experiments) and 81 ± 4% (SD; n = 6 experiments) of their body weight at the start of therapy, respectively. The latter schedule was associated with loose feces starting around week 8 of therapy, broken teeth and a high incidence of swelling of the orbital conjunctiva that developed late in the course of therapy. Given (d x 5)12, irinotecan caused complete regressions of all six neuroblastoma xenograft lines. Because mice tolerate significantly greater systemic exposure to SN-38 lactone than do patients (as determined by plasma AUC at the respective MTD), we evaluated the intermittent schedule of administration, reducing the dose/administration to determine the lowest dose levels that produced objective regressions of these neuroblastoma xenografts and determined the daily systemic exposure associated with these dose levels. In four lines examined objective responses were obtained at dose levels of 12.5 or 6.25 mg/kg. The daily plasma AUC exposures associated with minimum dose achieving response in NB1691 (12.5mg/kg), NB1643 (6.25 mg/kg) and NBEB (12.5 mg/kg) for irinotecan lactone were 219, 152 and 653 ng-h/ml, respectively; and for SN-38 lactone were 704, 418 and 987 ng-h/ml, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by oral administration and therapeutic activity is similar to i.v. irinotecan administered on similar schedules.

Original languageEnglish (US)
Pages (from-to)313-322
Number of pages10
JournalAnti-cancer drugs
Volume8
Issue number4
DOIs
StatePublished - 1997
Externally publishedYes

Keywords

  • Irinotecan
  • Neuroblastoma
  • Xenograft

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

Fingerprint

Dive into the research topics of 'Efficacy of oral irinotecan against neuroblastoma xenografts'. Together they form a unique fingerprint.

Cite this