Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. (September 2011)

• Record Type: Journal Article
• Authors: Amstutz, Ursula; Froehlich, Tanja K; Largiadèr, Carlo R
• Is Part Of: Pharmacogenomics. Volume 12:Number 9(2011)
• Page Start: 1321
• Page End: 1336
• Publication Date: 2011-09
• Subjects: 5-fluorouracil -- capecitabine -- dihydropyrimidine dehydrogenase -- DPYD -- gene polymorphism -- toxicity; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.11.72
• Languages: English
• ISSNs: 1462-2416

Abstract

The importance of polymorphisms in the dihydropyrimidine dehydrogenase (DPD) gene ( DPYD ) for the prediction of severe toxicity in 5-fluorouracil (5-FU) based chemotherapy has been controversially debated. As a key enzyme in the catabolism of 5-FU, DPD is the top candidate for pharmacogenetic studies on 5-FU toxicity, since a reduced DPD activity is thought to result in an increased half-life of the drug, and thus, an increased risk of toxicity. Here, we review the current knowledge on well-known and frequently studied DPYD variants such as the c.1905+1G>A splice site variant, as well as the recent discoveries of important functional variation in the noncoding regions of DPYD . We also outline future directions that are needed to further improve the risk assessment of 5-FU toxicity, in particular with respect to metabolic profiling and in the context of different combination therapeutic regimens, in which 5-FU is used today.