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[Cancer Research 60, 4206-4210, August 1, 2000]
© 2000 American Association for Cancer Research

Experimental Therapeutics

Activation of CPT-11 in Mice: Identification and Analysis of a Highly Effective Plasma Esterase1

Christopher L. Morton, Monika Wierdl, LaGora Oliver, Margaret K. Ma, Mary K. Danks, Clinton F. Stewart, Julie L. Eiseman2 and Philip M. Potter3

Departments of Molecular Pharmacology [C. L. M., M. W., L. O., M. K. D., P. M. P.] and Pharmaceutical Sciences [M. K. M., C. F. S.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, and Division of Experimental Therapeutics, Greenebaum Cancer Center, Baltimore, Maryland 21201-1595 [J. L. E.]

The camptothecin prodrug CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is converted by esterases to yield the potent topoisomerase I poison SN-38 (7-ethyl-10-hydroxycamptothecin). Recently, a mouse strain (Es1e) has been identified that demonstrates reduced plasma esterase activity, and we have monitored the ability of plasma from these mice to metabolize CPT-11. Total plasma esterase activity was reduced 3-fold in Es1emice in comparison to control mice, and this resulted in a 200-fold reduction in SN-38 production after incubation with CPT-11 in vitro. In addition, pharmacokinetic studies of CPT-11 and SN-38 in these animals demonstrated approximately 5-fold less conversion to SN-38. However, extracts derived from tissues from Es1e animals revealed total esterase activities similar to those of control mice, and these extracts metabolized CPT-11 with equal efficiency. Northern analysis of RNA isolated from organs indicated that the liver was the primary source of Es-1 gene expression and that very low levels of Es-1 RNA were present in Es1e mice. These results suggest that the reduced levels of Es-1 esterase present in Es1e mice are due to down-regulation of gene transcription, and that this plasma esterase is responsible for the majority of CPT-11 metabolism in mice.




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