Clinical implications of dihydropyrimidine dehydrogenase inhibition.
Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an important role in regulating the availability of 5-FU for anabolism. It is now clear that DPD also accounts for much of the variability observed with the therapeutic use of 5-FU, including variable drug levels during 24-hour infusion, erratic pharmacokinetics, variable bioavaialability, inconsistent toxicity, and variability in drug response (resistance). The use of DPD inhibitors has been explored as a means to improve 5-FU pharmacology. This article describes how drugs that modulate DPD activity have been used to develop a new class of orally administered fluoropyrimidines, now referred to as DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis for using four DIF drugs--uracil and tegafur (UFT), ethynyluracil, S-1, and BOF-A2--currently in clinical evaluation in the United States, is hereby reviewed. Early clinical data suggest that these drugs may achieve antitumor efficacy equivalent to that of conventional intravenously administered 5-FU therapy, with the additional advantages of reduced toxicity, less expense, and improved quality of life.
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Department of Pharmacology/Toxicology, University of Alabama Cancer Center, University of Alabama at Birmingham, USA.
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001682:Biological Availability; D042943:Dihydrouracil Dehydrogenase (NADP); D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005641:Tegafur / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005641:Tegafur; C073482:eniluracil; D014498:Uracil; C053194:Emitefur; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil