Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics

Abstract

A prominent example of the potential application of pharmacogenomics and pharmacogenetics to oncology is the study of dihydropyrimidine dehydrogenase (DPD) in 5-fluorouracil (5-FU) metabolism. 5-FU is currently one of the most widely administered chemotherapeutic agents used for the treatment of epithelial cancers. DPD is the rate-limiting enzyme in the catabolism and clearance of 5-FU. The observation of a familial linkage of DPD deficiency from a patient exhibiting 5-FU toxicity suggested a possible molecular basis for variations in 5-FU metabolism. Molecular studies have suggested there is a relationship between allelic variants in the DPYD gene (the gene that encodes DPD) and a deficiency in DPD activity, providing a potential pharmacogenetic basis for 5-FU toxicity. In the last decade, studies have correlated tumoral DPD activity with 5-FU response, suggesting it may be a useful pharmacogenomic marker of patient response to 5-FU-based chemotherapy. This article reviews the basis and discusses the challenges of pharmacogenetic and pharmacogenomic testing of DPD for the determination of 5-FU efficacy and toxicity.