title: Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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
authors.affiliation: Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK. jcummings@picr.man.ac.uk
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cummings
authors.forename: Brian T
authors.initials: BT
authors.lastname: Ethell
authors.forename: Lesley
authors.initials: L
authors.lastname: Jardine
authors.forename: Brian
authors.initials: B
authors.lastname: Burchell
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000880:Anthraquinones / Q000493:pharmacokinetics* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D003106:Colon / Q000201:enzymology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D006224:Cricetinae; D019008:Drug Resistance, Neoplasm; D020719:Glucuronides / Q000096:biosynthesis; D014453:Glucuronosyltransferase / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000099148:UGT1A1 Enzyme
chemical_list: D000880:Anthraquinones; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D014443:Tyrosine; D000099148:UGT1A1 Enzyme; C100645:NU-ICRF 505; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; C454320:UDP-glucuronosyltransferase, UGT1A8