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[Cancer Research 60, 4725-4728, September 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Proficient Metabolism of Irinotecan by a Human Intestinal Carboxylesterase1

Ruchi Khanna, Christopher L. Morton, Mary K. Danks and Philip M. Potter2

Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)] is metabolized by esterases to yield the potent topoisomerase I poison 7-ethyl-10-hydroxycamptothecin. One of the major side effects observed with CPT-11 is gastrointestinal toxicity, and we supposed that this might be due to local activation of CPT-11 within the gut. Carboxylesterase (CE) activity was detected in human gut biopsies, and extracts of these tissues converted CPT-11 to 7-ethyl-10-hydroxycamptothecin in vitro. Expression of a human intestinal CE cDNA in COS-7 cells produced extracts that demonstrated proficient CPT-11 activation and conferred sensitivity of cells to CPT-11. These results suggest that gut toxicity from CPT-11 may be due in part to direct drug conversion by CEs present within the small intestine.




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