AIMS: 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 metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by beta-glucuronidase may represent a significant pathway of SN-38 formation. METHODS: The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 microm) was measured in homogenates of human colorectal tumour, and matched normal colon mucosa from 21 patients). RESULTS: The rate of conversion of irinotecan (9.6 microm) was lower in tumour tissue than matched normal colon mucosa samples (0.30+/-0.14 pmol min-1 mg-1 protein and 0.77+/-0.59 pmol min-1 mg-1 protein, respectively; P<0.005). In contrast, no significant difference was observed in beta-glucuronidase activity between tumour and matched normal colon samples (4.56+/-6.9 pmol min-1 mg-1 protein and 3.62+/-2.95 pmol min-1 mg-1 protein, respectively, using 9.6 microm SN-38 glucuronide; P>0.05). beta-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2>0.23, P<0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P<0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable. CONCLUSIONS: Tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo.
AIMS: 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 metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by beta-glucuronidase may represent a significant pathway of SN-38 formation. METHODS: The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 microm) was measured in homogenates of humancolorectal tumour, and matched normal colon mucosa from 21 patients). RESULTS: The rate of conversion of irinotecan (9.6 microm) was lower in tumour tissue than matched normal colon mucosa samples (0.30+/-0.14 pmol min-1 mg-1 protein and 0.77+/-0.59 pmol min-1 mg-1 protein, respectively; P<0.005). In contrast, no significant difference was observed in beta-glucuronidase activity between tumour and matched normal colon samples (4.56+/-6.9 pmol min-1 mg-1 protein and 3.62+/-2.95 pmol min-1 mg-1 protein, respectively, using 9.6 microm SN-38 glucuronide; P>0.05). beta-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2>0.23, P<0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P<0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable. CONCLUSIONS:Tumourbeta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo.
Authors: Helen M Dodds; Peter J Tobin; Clinton F Stewart; Pam Cheshire; Suzan Hanna; Peter Houghton; Laurent P Rivory Journal: J Pharmacol Exp Ther Date: 2002-11 Impact factor: 4.030
Authors: B Sperker; U Werner; T E Mürdter; C Tekkaya; P Fritz; R Wacke; U Adam; M Gerken; B Drewelow; H K Kroemer Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2000-08 Impact factor: 3.000
Authors: S Guichard; C Terret; I Hennebelle; I Lochon; P Chevreau; E Frétigny; J Selves; E Chatelut; R Bugat; P Canal Journal: Br J Cancer Date: 1999-05 Impact factor: 7.640
Authors: P H Houba; E Boven; I H van der Meulen-Muileman; R G Leenders; J W Scheeren; H M Pinedo; H J Haisma Journal: Br J Cancer Date: 2001-02 Impact factor: 7.640
Authors: Adam B Roberts; Bret D Wallace; Madhu Kumar Venkatesh; Sridhar Mani; Matthew R Redinbo Journal: Mol Pharmacol Date: 2013-05-20 Impact factor: 4.436
Authors: K T Tan; R Rakheja; C Plewes; P Mondal; H Lim; S Ahmed; E Lee; R Otani; Y Luo; J Shaw Journal: Gastroenterol Res Pract Date: 2019-11-04 Impact factor: 2.260