Clinical Implications of Dihydropyrimidine Dehydrogenase Inhibition

ABSTRACT: 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 bioavailability, 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. [ONCOLOGY 7(Suppl 3):17-21, 1999]

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