Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.
dc.contributor.author | Cummings, Jeffrey | |
dc.contributor.author | Ethell, Brian T | |
dc.contributor.author | Jardine, Lesley | |
dc.contributor.author | Burchell, Brian | |
dc.date.accessioned | 2009-07-09T12:19:29Z | |
dc.date.available | 2009-07-09T12:19:29Z | |
dc.date.issued | 2006 | |
dc.identifier.citation | Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon., 26 (3B):2189-96 Anticancer Res. | en |
dc.identifier.issn | 0250-7005 | |
dc.identifier.pmid | 16821585 | |
dc.identifier.uri | http://hdl.handle.net/10541/73078 | |
dc.description.abstract | 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 | |
dc.language.iso | en | en |
dc.subject | Colonic Cancer | en |
dc.subject.mesh | Adenocarcinoma | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Anthraquinones | |
dc.subject.mesh | Antineoplastic Agents, Phytogenic | |
dc.subject.mesh | Camptothecin | |
dc.subject.mesh | Colon | |
dc.subject.mesh | Colonic Neoplasms | |
dc.subject.mesh | Cricetinae | |
dc.subject.mesh | Drug Resistance, Neoplasm | |
dc.subject.mesh | Glucuronides | |
dc.subject.mesh | Glucuronosyltransferase | |
dc.subject.mesh | HT29 Cells | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Tyrosine | |
dc.title | Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon. | en |
dc.type | Article | en |
dc.contributor.department | Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK. jcummings@picr.man.ac.uk | en |
dc.identifier.journal | Anticancer Research | en |
html.description.abstract | 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 |