Document Detail

Irinotecan activation by human carboxylesterases in colorectal adenocarcinoma cells.
MedLine Citation:
PMID:  12171903     Owner:  NLM     Status:  MEDLINE    
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 micro M and 6.8 micro M, respectively). Our data further support the notion that hCE-2 plays a substantial role in irinotecan activation in human tissue at relevant pharmacologic concentrations.
Michael H Wu; Bingfang Yan; Rod Humerickhouse; M Eileen Dolan
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  8     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-08-12     Completed Date:  2003-02-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2696-700     Citation Subset:  IM    
Section of Hematology-Oncology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, Illinois 60637-1470, USA.
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MeSH Terms
Antineoplastic Agents, Phytogenic / pharmacology
Blotting, Western
Camptothecin / analogs & derivatives*,  pharmacology*
Carboxylic Ester Hydrolases / chemistry,  genetics,  metabolism*
Cloning, Molecular
Colorectal Neoplasms / drug therapy*,  metabolism*
DNA, Complementary / metabolism
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Enzyme Inhibitors / pharmacology
Gene Library
Isoelectric Focusing
Protein Isoforms
Time Factors
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/DNA, Complementary; 0/Enzyme Inhibitors; 0/Protein Isoforms; 100286-90-6/irinotecan; 7689-03-4/Camptothecin; EC 3.1.1.-/Carboxylic Ester Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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