Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon.
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
Cummings
Jeffrey
J
Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK. jcummings@picr.man.ac.uk
Ethell
Brian T
BT
Jardine
Lesley
L
Burchell
Brian
B
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
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