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

Cancer Chemother Pharmacol. 2005 Dec;56(6):629-36. doi: 10.1007/s00280-005-1027-y. Epub 2005 May 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Body Weight / drug effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / blood
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Dose-Response Relationship, Drug
  • Esterases / deficiency*
  • Esterases / genetics
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / enzymology
  • Humans
  • Irinotecan
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Rhabdomyosarcoma / drug therapy
  • Rhabdomyosarcoma / pathology
  • Sarcoma, Experimental / drug therapy*
  • Sarcoma, Experimental / metabolism
  • Sarcoma, Experimental / pathology


  • Antineoplastic Agents, Phytogenic
  • Irinotecan
  • Esterases
  • Camptothecin