Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice

Christopher L. Morton, Lisa Iacono, Janice L. Hyatt, Kody R. Taylor, Pamela J. Cheshire, Peter J. Houghton, Mary K. Danks, Clinton F. Stewart, Philip M. Potter

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Purpose: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. Experimental design: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. Results: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. Conclusions: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.

Original languageEnglish (US)
Pages (from-to)629-636
Number of pages8
JournalCancer chemotherapy and pharmacology
Volume56
Issue number6
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

Keywords

  • CPT-11
  • Es1 mice
  • SN-38
  • carboxylesterase

ASJC Scopus subject areas

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

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    Morton, C. L., Iacono, L., Hyatt, J. L., Taylor, K. R., Cheshire, P. J., Houghton, P. J., Danks, M. K., Stewart, C. F., & Potter, P. M. (2005). Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer chemotherapy and pharmacology, 56(6), 629-636. https://doi.org/10.1007/s00280-005-1027-y