Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics.
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.
Mattison
Lori K
LK
Department of Pharmacology and Toxicology, Room 101, Volker Hall, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Soong
Richie
R
Diasio
Robert B
RB
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000633:toxicity; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000378:metabolism* / Q000633:toxicity; D005819:Genetic Markers; D023281:Genomics; D006801:Humans; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics
D000964:Antimetabolites, Antineoplastic; D005819:Genetic Markers; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil