Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.

2.50
Hdl Handle:
http://hdl.handle.net/10541/73078
Title:
Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.
Authors:
Cummings, Jeffrey; Ethell, Brian T; Jardine, Lesley; Burchell, Brian
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
Affiliation:
Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK. jcummings@picr.man.ac.uk
Citation:
Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon., 26 (3B):2189-96 Anticancer Res.
Journal:
Anticancer Research
Issue Date:
2006
URI:
http://hdl.handle.net/10541/73078
PubMed ID:
16821585
Type:
Article
Language:
en
ISSN:
0250-7005
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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 remainen
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
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