Dihydropyrimidine dehydrogenase polymorphisms and fluoropyrimidine toxicity: ready for routine clinical application within personalized medicine?

Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumorsand remain the backbone of many combination regimens.Despite their clinical benefit, fluoropyrimidinesare associated with gastrointestinal and hematologictoxicities, which often lead to treatment discontinuation.5-FU undergoes complex metabolism, dihydropyrimidinedehydrogenase (DPD) being the rate-limiting enzyme ofinactivation of 5-FU and its prodrugs. Several studieshave demonstrated significant associations betweensevere toxicities by fluoropyrimidines and germlinepolymorphisms of DPD gene. To date, more than 30SNPs and deletions have been identified within DPD,the majority of these variants having no functionalconsequences on enzymatic activity. However, theidentification of deficient DPD genotypes may helpidentify poor-metabolizer patients at risk of developingpotentially life-threatening toxicities after standard dosesof fluoropyrimidines.