Background: Glucuronidation represents a novel mechanism of intrinsic drug resistance in colon cancer cells. To safely reverse this mechanism in vivo, it is essential to identify which isoforms of UDP-glucuronosyltransferases are responsible for catalysing this drug metabolism in tumour tissue.
Materials And Methods: LC-MS was applied to measure rates of glucuronidation of two anticancer compounds (SN-38 and NU/ICRF 505) by patient colon cancer biopsies and paired normal colon.
Results: Three independent lines of enquiry indicated that, in the tumour specimens, SN-38 was glucuronidated primarily by UGT1A1, the isozyme generally recognised as being responsible for hepatic detoxification of this compound, while with NU/ICRF 505 two candidate isoforms emerged - UGT1A8 and/or UGT1A10 - both of which are not normally expressed in the liver.
Conclusion: These data suggest that tumour selective modulation of this drug resistance mechanism in patients may be feasible with NU/ICRF 505 but more difficult to realise with SN-38. De novo drug resistance is recognised as contributing significantly to the poor response rates of colorectal cancer (CRC) to chemotherapy (1). Nonetheless, the underlying mechanisms responsible for drug insensitivity remain
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Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.
Anticancer Res
July 2006
Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK.
Background: Glucuronidation represents a novel mechanism of intrinsic drug resistance in colon cancer cells. To safely reverse this mechanism in vivo, it is essential to identify which isoforms of UDP-glucuronosyltransferases are responsible for catalysing this drug metabolism in tumour tissue.
Materials And Methods: LC-MS was applied to measure rates of glucuronidation of two anticancer compounds (SN-38 and NU/ICRF 505) by patient colon cancer biopsies and paired normal colon.
Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives.
Cancer Res
December 2003
Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, United Kingdom.
Article Synopsis
- Colon cancer is resistant to chemotherapy due to mechanisms like glucuronidation, which involves the enzyme UDP-glucuronosyltransferases (UGTs).
- Research identified UGT1A9 as the key enzyme in glucuronidating two topoisomerase I inhibitors, enhancing drug resistance in colon cancer cells.
- Inhibiting this glucuronidation can significantly increase drug effectiveness, suggesting that dietary substances and certain medications could potentially alter drug resistance in colon cancer.
Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins.
Biochem Pharmacol
January 2004
Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, EH4 2XR, Edinburgh, UK.
We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in this mechanism. The ability of transport proteins to recognise NU/ICRF 505 as a substrate was evaluated in model systems either transfected with breast cancer-resistance protein 1 (Bcrp1), multidrug-resistance protein 2 (Mrp2) or Mrp3, or overexpressing MRP1 or P-170 glycoprotein. Results from chemosensitivity assays suggested that NU/ICRF 505 was not a substrate for any of the above proteins.
View Article and Find Full Text PDFEnhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation.
Biochem Pharmacol
February 2002
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, EH4 2XU, Edinburgh, UK.
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.
View Article and Find Full Text PDFCell cycle effects of the novel topoisomerase I inhibitor NU/ICRF 505 in a panel of Chinese hamster ovary cell lines.
Eur J Cancer
February 1997
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
The effect of the novel topoisomerase I inhibitor NU/ICRF 505 (20 microM, approximate IC50 concentration) on the cell cycle was studied by flow cytometry in four Chinese hamster ovary (CHO) cell lines. Postdrug treated cells were incubated with optimal concentrations of cytochalasin B to prevent re-entry of daughter cells into the cell cycle. NU/ICRF 505 had no significant effect on cell cycle distribution in the parent cell line (CHO-K1) and two mutants hypersensitive to topo II inhibitors (ADR-1, ADR-3), all of which express similar levels of topo I protein.
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