title: Characterization of CPT-11 converting carboxylesterase activity in colon tumor and normal tissues: comparison with p-nitro-phenylacetate converting carboxylesterase activity.
abstract: Irinotecan (CPT-11) is a topoisomerase I inhibitor commonly used in the treatment of colorectal tumors. It is a prodrug, converted to an active metabolite, SN-38, by carboxylesterases (CEs). CEs are ubiquitary enzymes that react with numerous substrates. A specific CPT-11 converting enzyme was isolated from rat serum, with different kinetic properties than other CEs. We determined kinetic properties of specific CPT-11 CE activity (CPT-CE) in human normal liver and colon tumors. Km were very similar (3.4 microM in liver and 3.8 microM in colon tumors), but Vmax was higher in liver (2.7 pmol/min/mg protein) than in colon tumor (1.7 pmol/min/mg protein). CPT-CE and total CE (using p-nitro-phenylacetate as substrate) were weakly correlated in colon tumors. The large interpatient variability observed in liver CPT-CE activity could play a potential role in the pharmacokinetic variability observed with irinotecan.
authors.affiliation: Groupe de Pharmacologie Clinique et Expérimentale (EA 3035), Institut Claudius Regaud, Toulouse, France.
authors.forename: I
authors.initials: I
authors.lastname: Hennebelle
authors.forename: C
authors.initials: C
authors.lastname: Terret
authors.forename: E
authors.initials: E
authors.lastname: Chatelut
authors.forename: R
authors.initials: R
authors.lastname: Bugat
authors.forename: P
authors.initials: P
authors.lastname: Canal
authors.forename: S
authors.initials: S
authors.lastname: Guichard
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009596:Nitrophenols / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C008642:4-nitrophenyl acetate; C072888:CPT-11 converting enzyme; D002265:Carboxylic Ester Hydrolases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin