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 journalArticlepeer-review

60 Scopus citations


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
Issue number6
StatePublished - Dec 2005
Externally publishedYes


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

ASJC Scopus subject areas

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


Dive into the research topics of 'Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice'. Together they form a unique fingerprint.

Cite this