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dc.contributor.authorCummings, Jeffrey
dc.contributor.authorEthell, Brian T
dc.contributor.authorJardine, Lesley
dc.contributor.authorBurchell, Brian
dc.date.accessioned2009-07-09T12:19:29Z
dc.date.available2009-07-09T12:19:29Z
dc.date.issued2006
dc.identifier.citationGlucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon., 26 (3B):2189-96 Anticancer Res.en
dc.identifier.issn0250-7005
dc.identifier.pmid16821585
dc.identifier.urihttp://hdl.handle.net/10541/73078
dc.description.abstractBACKGROUND: 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.isoenen
dc.subjectColonic Canceren
dc.subject.meshAdenocarcinoma
dc.subject.meshAnimals
dc.subject.meshAnthraquinones
dc.subject.meshAntineoplastic Agents, Phytogenic
dc.subject.meshCamptothecin
dc.subject.meshColon
dc.subject.meshColonic Neoplasms
dc.subject.meshCricetinae
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshGlucuronides
dc.subject.meshGlucuronosyltransferase
dc.subject.meshHT29 Cells
dc.subject.meshHumans
dc.subject.meshTyrosine
dc.titleGlucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK. jcummings@picr.man.ac.uken
dc.identifier.journalAnticancer Researchen
html.description.abstractBACKGROUND: 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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