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.
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Abbreviations
- AUC0-∞:
-
Area under the concentration-time curve from time 0 to infinity
- CE:
-
Carboxylesterase
- CL:
-
Clearance
- CPT-11:
-
Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
- HPLC:
-
High-performance liquid chromatography
- o-NPA:
-
o-nitrophenyl acetate
- SN-38:
-
7-ethyl-10-hydroxycamptothecin
- SN-38G:
-
SN-38 glucuronide
- V c :
-
Volume of the central compartment
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Acknowledgments
We thank Dr. J. P. McGovren for the gifts of CPT-11 and SN-38, and Yakult Honsha for SN-38G. This work was supported in part by NIH grants CA76202, CA79763, CA23099, the Cancer Center Core Grant CA21765 and the American Lebanese Syrian Associated Charities.
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Morton, C.L., Iacono, L., Hyatt, J.L. et al. Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer Chemother Pharmacol 56, 629–636 (2005). https://doi.org/10.1007/s00280-005-1027-y
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DOI: https://doi.org/10.1007/s00280-005-1027-y