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Irinotecan Activation by Human Carboxylesterases in Colorectal Adenocarcinoma Cells¹

Section of Hematology-Oncology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, Illinois [M. H. W., R. H., M. E. D.] and Section of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Rhode Island, Kingston, Rhode Island [B. Y.]

Carboxylesterases play a critical role in the bioactivation of the anticancer prodrug irinotecan {7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin; CPT-11} into its active metabolite SN-38 (ethyl-10-hydroxy-camptothecin). We reported recently that human carboxylesterase-2 (hCE-2) is a higher-affinity, higher-velocity enzyme for irinotecan hydrolysis when compared with hCE-1. To further investigate the role of these isoforms, we cloned both cDNAs into the human colorectal adenocarcinoma cell line HT29. Extracts of HT29 cells transfected with hCE-2 exhibited significantly higher irinotecan hydrolysis (5.2 pmol/mg protein/hr) than hCE-1 (1.0 pmol/mg protein/hr). HT29 cells over-expressing hCE-2 were more sensitive to the toxic effects of irinotecan than cells expressing hCE-1 (EC₅₀ = 0.3 µM and 6.8 µM, respectively). Our data further support the notion that hCE-2 plays a substantial role in irinotecan activation in human tissue at relevant pharmacologic concentrations.

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