Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy.
Through the use of pharmacogenetic studies, interindividual variability in response (efficacy and toxicity) to 5-fluorouracil (5-FU) chemotherapy has been linked to the rate-limiting enzyme in the drug's catabolic pathway, known as dihydropyrimidine dehydrogenase (DPD). This pharmacogenetic syndrome, known as "DPD deficiency," results in excessive amounts of 5-FU available to be anabolized to its active metabolites and is relatively undetectable by clinical observation prior to 5-FU administration. Extensive studies have associated both profound and partial deficiency in DPD activity with severe, unanticipated toxicity after 5-FU administration, while research on the molecular basis behind DPD deficiency has been linked to various sequence variants of the DPYD gene. Due to the widespread use of 5-FU, the severity of toxicity associated with DPD deficiency, and the prevalence of DPD deficiency in the population, extensive research is continually being performed to develop quick and accurate phenotypic and genotypic assays suitable for clinical settings that would allow clinicians to identify patients susceptible to adverse 5-FU reactions.
Lee
Adam
A
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA.
Ezzeldin
Hany
H
Fourie
Jeanne
J
Diasio
Robert
R
D000931:Antidotes / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D004252:DNA Mutational Analysis; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D003875:Drug Eruptions / Q000209:etiology; D005334:Fever / Q000139:chemically induced; D005467:Floxuridine / Q000031:analogs & derivatives / Q000378:metabolism; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008403:Mass Screening; D052016:Mucositis / Q000139:chemically induced; D009154:Mutation; D011355:Prodrugs / Q000493:pharmacokinetics*; D011741:Pyrimidine Nucleosides / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000378:metabolism; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D003856:Deoxyuracil Nucleotides; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; C522804:fluorodeoxyuridine triphosphate; D005467:Floxuridine; C025635:5-fluorouridine 5'-triphosphate; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil; D014544:Uridine Triphosphate