Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan.
The prodrug irinotecan is an active agent for the treatment of advanced colorectal cancer and a number of other solid tumors. Irinotecan is converted in vivo to SN-38 (7-ethyl-10-hydroxy-camptothecin), the active metabolite that causes cell death, by human liver carboxylesterases. Previous studies suggest that human carboxylesterase 2 (CES2) is the key activating isoform. Although conversion of irinotecan to SN-38 by liver carboxylesterase is an inefficient process, clinical data indicate that irinotecan has significant antitumor activity. This scenario raises the possibility that local conversion of irinotecan to SN-38 by CES2 in tumor tissues might occur. The expression profile of CES2 protein in human tumor tissues was evaluated in a tissue array of 18 different types of human cancer and in a panel of normal human liver samples by immunohistochemistry and Western blot, respectively. Cytosolic CES2 expression was observed in 101 of 154 tumors (66%) and 55 of 60 normal tissues (92%). Among the 18 types of tumors analyzed, 2 types (gallbladder tumor and lymphoma) did not express CES2, 5 types expressed weak CES2, and 11 types expressed moderate to intense CES2. In functional studies, CES2 protein was highly variable among liver samples, with a 15-fold range in cytosol and a 3-fold range in microsome fractions. Liver microsomal CES2 protein expression was significantly correlated with irinotecan activation to SN-38 (R(s) = 0.70; P = 0.007). This study confirms that CES2 is a key enzyme for irinotecan activation. Tumor CES2 expression may contribute to variable response to irinotecan chemotherapy for solid tumors.
Xu
Guang
G
Department of Medicine, Washington University School of Medicine, and The Siteman Cancer Center, St. Louis, Missouri 63110, USA.
Zhang
Wanghai
W
Ma
Margaret K
MK
McLeod
Howard L
HL
D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D007700:Kinetics; D008099:Liver / Q000473:pathology; D008862:Microsomes, Liver / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020033:Protein Isoforms; D014407:Tumor Cells, Cultured
D020033:Protein Isoforms; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D002166:Camptothecin