CPT-11 is a highly effective, camptothecin-based anticancer agent that is currently approved for the treatment of colon cancer. This compound is a prodrug and is activated by carboxylesterases to yield SN-38, a potent topoisomerase I poison. The dose limiting toxicity for CPT-11 is delayed diarrhea that occurs 48-96 hours following administration. This is thought to arise, in part, from direct activation of CPT-11, that is secreted in the bile, by a human intestinal carboxylesterase (CE) that is highly expressed in the small intestine. We hypothesize that by inhibiting this enzyme, reduced SN-38 will be produced from drug hydrolysis in the gut, thereby reducing the toxicity associated with CPT-11 treatment. The goals of this application are therefore to develop selective CE inhibitors that can be used to ameliorate the toxicity associated with CPT-11 administration. Highly potent, non-toxic small molecule inhibitors based upon the prototypical compound benzil have been identified, and we propose to develop these agents for use in inhibition of the human intestinal CE (hiCE). NMR, x-ray crystallography, medicinal chemistry, QSAR, biochemical and in vivo approaches will all be employed to validate the efficacy of suitable compounds The specific aims of this application are: 1) to determine the mechanism of CE inhibition by benzil;2) to develop water-soluble analogues of benzil;3) to assess the biochemical and biological properties of these compounds;and 4) assess their efficacy at modulating CPT-11-induced toxicity in a plasma esterase-deficient mouse model where hiCE is expressed in the mouse intestine. We believe that, if successful, these studies will provide reagents that can ameliorate the delayed diarrhea associated with CPT-11 administration, and potentially allow dose intensification of the drug. This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent.
These studies will identify and characterize novel drugs that can reduce the toxicity associated with CPT-11 treatment. Since this chemotherapeutic agent is widely used for cancer therapy, any approaches that reduce the side-effects of this drug will be highly desirable. We propose to develop such compounds that should have applicability to a wide variety of malignancies.
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|Yu, Xiaozhen; Sigler, Sara C; Hossain, Delwar et al. (2012) Global and local molecular dynamics of a bacterial carboxylesterase provide insight into its catalytic mechanism. J Mol Model 18:2869-83|
|Hatfield, M Jason; Potter, Philip M (2011) Carboxylesterase inhibitors. Expert Opin Ther Pat 21:1159-71|
|Hatfield, M Jason; Tsurkan, Lyudmila; Garrett, Michael et al. (2011) Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11. Biochem Pharmacol 81:24-31|
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