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The Role of Rat Serum Carboxylesterase in the Activation of Paclitaxel and Camptothecin Prodrugs

Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121 [P. D. S., H. M., I. S. F., H. P. S.], and Department of Entomology and Environmental Toxicology, University of California at Davis, Davis, California 95616 [B. A. T., B. D. H.]

Paclitaxel-2-ethylcarbonate (PC) is a prototype for a family of paclitaxel prodrugs that have significant levels of antitumor activities in rodent models for human cancer. In this study, an enzyme responsible for the conversion of PC to paclitaxel was purified from rat serum. N-terminal amino acid sequence analysis indicated that the isolated enzyme was rat serum carboxylesterase. This enzyme was shown to significantly enhance the cytotoxic activities of both PC and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a water-soluble analogue of camptothecin, on lung carcinoma and melanoma cell lines. Rat serum carboxylesterase may have applications for the site-specific delivery of anticancer drugs to tumor masses.

¹ To whom requests for reprints should be addressed, at Bristol-Myers Squibb Pharmaceutical Research Institute, 3005 First Avenue, Seattle, WA 98121.

Received 1/15/96. Accepted 2/15/96.

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