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Enhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation

Authors :
Janet S. Macpherson
John F. Smyth
Brian Burchell
Jeffrey Cummings
Duncan I. Jodrell
Brian T. Ethell
Gary Boyd
Source :
Biochemical Pharmacology. 63:607-613
Publication Year :
2002
Publisher :
Elsevier BV, 2002.

Abstract

As part of a program to identify novel mechanisms of resistance to topoisomerase I (topo I) inhibitors, the cellular pharmacology of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of clinically used irinotecan (CPT-11) and NU/ICRF 505, an anthraquinone-tyrosine conjugate, has been investigated in two human colorectal cancer (CRC) cell lines. Two novel metabolites of NU/ICRF 505 (M1 and M2) and a single metabolite of SN-38 (M1) were detected by high performance liquid chromatography in the culture medium of HT29 cells but were absent in HCT116 cells. Identities of all three metabolites were established by a combination of biochemical and physicochemical techniques. M1 of SN-38 was the C10-(beta)-glucuronide of the parent lactone while M1 of NU/ICRF 505 was the C4-O-glucuronide and M2 the tyrosine-O-glucuronide, both of the parent compound. Drug transport studies revealed that by 24hr HT29 cells had effectively cleared 82.5% of NU/ICRF 505 (10 microM) into the culture medium as the two glucuronides. In contrast, intracellular concentrations of NU/ICRF 505 were maintained in HCT116 cells in the absence of glucuronidation at a level 550 times greater than in HT29 cells. HT29 cells cleared 40.9% of SN-38 (1 microM) as the glucuronide to the culture medium, while the parent drug was maintained at a level 2-fold greater in HCT116 cells. Enhanced drug clearance due to glucuronidation may contribute to intrinsic drug resistance of human CRC.

Details

ISSN :
00062952
Volume :
63
Database :
OpenAIRE
Journal :
Biochemical Pharmacology
Accession number :
edsair.doi.dedup.....914e77674dc4f64597caea2854c3fa3c
Full Text :
https://doi.org/10.1016/s0006-2952(01)00812-7