title: The relative contributions of carboxylesterase and beta-glucuronidase in the formation of SN-38 in human colorectal tumours.
abstract: Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is subsequently metabolised to its inactive glucuronide, SN-38G, which can however be reactivated to SN-38 by beta-glucuronidase. The purpose of this study was to examine the role of carboxylesterases and beta-glucuronidase in the in vitro production of SN-38 in human colorectal tumours. The production of SN-38 from CPT-11 and SN-38G was measured by HPLC in human colorectal tumour homogenates. Carboxylesterase and beta-glucuronidase activities were found to be lower in tumour tissues compared to matched normal colon mucosa samples. In colorectal tumour, beta-glucuronidase and carboxylesterase-mediated SN-38 production rates were comparable at clinically relevant concentrations of SN-38G and CPT-11, respectively. Therefore, tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo, particularly during prolonged infusions of CPT-11.
authors.affiliation: Department of Pharmacology, University of Sydney, New South Wales, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tobin
authors.forename: Helen M
authors.initials: HM
authors.lastname: Dodds
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.forename: Margaret
authors.initials: M
authors.lastname: Schnitzler
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Rivory
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043182:Carboxylesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D000077146:Irinotecan; D009092:Mucous Membrane / Q000378:metabolism; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D043182:Carboxylesterase; D005966:Glucuronidase; D002166:Camptothecin