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

50 Citations (Scopus)

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

Fingerprint

irinotecan
Esterases
Thermodynamic properties
Chemical activation
Plasmas
Pharmacokinetics
Heterografts
Carboxylesterase
Animals
Metabolites
Tumors
Bearings (structural)
Heterologous Transplantation

Keywords

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

ASJC Scopus subject areas

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

Cite this

Morton, C. L., Iacono, L., Hyatt, J. L., Taylor, K. R., Cheshire, P. J., Houghton, P. J., ... 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

Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. / Morton, Christopher L.; Iacono, Lisa; Hyatt, Janice L.; Taylor, Kody R.; Cheshire, Pamela J.; Houghton, Peter J; Danks, Mary K.; Stewart, Clinton F.; Potter, Philip M.

In: Cancer Chemotherapy and Pharmacology, Vol. 56, No. 6, 01.12.2005, p. 629-636.

Research output: Contribution to journalArticle

Morton, CL, Iacono, L, Hyatt, JL, Taylor, KR, Cheshire, PJ, Houghton, PJ, Danks, MK, Stewart, CF & Potter, PM 2005, 'Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice', Cancer Chemotherapy and Pharmacology, vol. 56, no. 6, pp. 629-636. https://doi.org/10.1007/s00280-005-1027-y
Morton, Christopher L. ; Iacono, Lisa ; Hyatt, Janice L. ; Taylor, Kody R. ; Cheshire, Pamela J. ; Houghton, Peter J ; Danks, Mary K. ; Stewart, Clinton F. ; Potter, Philip M. / Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. In: Cancer Chemotherapy and Pharmacology. 2005 ; Vol. 56, No. 6. pp. 629-636.
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