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[Cancer Research 60, 1189-1192, March 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Characterization of CPT-11 Hydrolysis by Human Liver Carboxylesterase Isoforms hCE-1 and hCE-21

Rod Humerickhouse, Karen Lohrbach, Lin Li, William F. Bosron and M. Eileen Dolan2

Department of Medicine [R. H., K. L., M. E. D.], Committee on Clinical Pharmacology [R. H., M. E. D.], and Cancer Research Center [M. E. D.], University of Chicago, Chicago, Illinois 60637-1470, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [L. L., W. F. B.]

7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (irinotecan; CPT-11) is a prodrug activated by carboxylesterase enzymes. We characterized the hydrolysis of CPT-11 by two recently identified human carboxylesterase (hCE) enzymes, hCE-1 and hCE-2. Km and Vmax for hCE-1 and hCE-2 are 43 µM and 0.53 nmol/min/mg protein and 3.4 µM and 2.5 nmol/min/mg protein, respectively. hCE-2 has a 12.5-fold higher affinity for CPT-11 and a 5-fold higher maximal rate of CPT-11 hydrolysis when compared with hCE-1. In cytotoxicity assays, incubation of 1 µM CPT-11 with hCE-2 (3.6 µg/ml) resulted in a 60% reduction in survival of SQ20b cells. No significant reduction in cell survival was observed after incubation of CPT-11 with hCE-1. These data indicate that hCE-2 is a high-affinity, high-velocity enzyme with respect to CPT-11. hCE-2 likely plays a substantial role in CPT-11 activation in human liver at relevant pharmacological concentrations.




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