Journal article
Phenotypic Profiling of DPYD Variations Relevant to 5-Fluorouracil Sensitivity Using Real-time Cellular Analysis and In Vitro Measurement of Enzyme Activity
Cancer research (Chicago, Ill.), Vol.73(6), pp.1958-1968
03/15/2013
DOI: 10.1158/0008-5472.CAN-12-3858
PMCID: PMC3602211
PMID: 23328581
Abstract
In the 45 years since its development, the pyrimidine analog 5-fluorouracil (5-FU) has become an integral component of many cancer treatments, most notably for the management of colorectal cancer. An appreciable fraction of patients who receive 5-FU suffer severe adverse toxicities, which in extreme cases may result in death. Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Clinical studies have suggested that genetic variations in DPYD increase the risk for 5-FU toxicity, however, there is not a clear consensus about which variations are relevant predictors. In the present study, DPYD variants were expressed in mammalian cells, and the enzymatic activity of expressed protein was determined relative to wild-type (WT). Relative sensitivity to 5-FU for cells expressing DPYD variations was also measured. The DPYD*2A variant (exon 14 deletion caused by IVS14+1G>A) was confirmed to be catalytically inactive. Compared with WT, two variants, S534N and C29R, showed significantly higher enzymatic activity. Cells expressing S534N were more resistant to 5-FU-mediated toxicity compared with cells expressing WT DPYD. These findings support the hypothesis that selected DPYD alleles are protective against severe 5-FU toxicity, and, as a consequence, may decrease the effectiveness of 5-FU an antitumor drug in carriers. In addition, this study shows a method that may be useful for phenotyping other genetic variations in pharmacologically relevant pathways. Cancer Res; 73(6); 1958-68. (C)2013 AACR.
Details
- Title: Subtitle
- Phenotypic Profiling of DPYD Variations Relevant to 5-Fluorouracil Sensitivity Using Real-time Cellular Analysis and In Vitro Measurement of Enzyme Activity
- Creators
- Steven M. Offer - Mayo ClinicNatalie J. Wegner - Mayo ClinicCroix Fossum - Mayo ClinicKangsheng Wang - Mayo ClinicRobert B. Diasio - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.73(6), pp.1958-1968
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/0008-5472.CAN-12-3858
- PMID
- 23328581
- PMCID
- PMC3602211
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Number of pages
- 11
- Grant note
- CA116964 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA116964 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 03/15/2013
- Academic Unit
- Pathology
- Record Identifier
- 9984618631002771
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