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Updated: Aug 7, 2026
Quantification of Colonic Stem Cell Mutations
Published on: September 25, 2015
Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon
Jeffrey Cummings1, Brian T Ethell, Lesley Jardine
1Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Edinburgh, UK. jcummings@picr.man.ac.uk
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
Insights
Colon cancer cells resist drugs via glucuronidation. Identifying specific UDP-glucuronosyltransferases (UGTs) in tumors is key to reversing this resistance, with UGT1A1, UGT1A8, and UGT1A10 showing distinct roles.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Glucuronidation is an emerging mechanism of intrinsic drug resistance in colon cancer.
- Understanding the specific UDP-glucuronosyltransferase (UGT) isoforms involved is crucial for developing effective chemotherapy strategies.
- Drug resistance significantly contributes to poor treatment outcomes in colorectal cancer (CRC).
Purpose of the Study:
- To identify the specific UDP-glucuronosyltransferase (UGT) isoforms responsible for drug metabolism in colon cancer tissue.
- To investigate the feasibility of reversing drug resistance by targeting these UGT isoforms in vivo.
Main Methods:
- Liquid chromatography-mass spectrometry (LC-MS) was employed to quantify glucuronidation rates.
- Patient-derived colon cancer biopsies and paired normal colon tissues were analyzed.
- Two anticancer compounds, SN-38 and NU/ICRF 505, were used to assess glucuronidation activity.
Main Results:
- In tumor specimens, SN-38 was primarily glucuronidated by UGT1A1.
- NU/ICRF 505 glucuronidation involved UGT1A8 and/or UGT1A10, isoforms not typically found in the liver.
- Differential UGT isoform expression was observed between tumor and normal colon tissues.
Conclusions:
- Tumor-specific modulation of glucuronidation-mediated drug resistance appears feasible with NU/ICRF 505.
- Targeting SN-38 resistance may be more challenging due to its primary metabolism by UGT1A1.
- These findings offer potential therapeutic strategies for overcoming drug resistance in colorectal cancer.
