Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown....

5-FU is one of the most commonly prescribed anticancer agents having notable activity in the treatment of cancers arising from the breast, gastrointestinal tract, and head and neck. The metabolism, mechanisms of action and resistance, and pharmacokinetics of 5-FU have been extensively investigated since its synthesis over 4 decades ago. Despite a longstanding knowledge of the metabolic pathways...

Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), accounting for catabolism of over 85% of an administered dose of 5-FU. DPD plays an important role in regulating the availability of 5-FU for anabolism. DPD also accounts for much of the variability observed with the therapeutic use of 5-FU. This includes variable 5-FU levels ov...

Deficiency of the pyrimidine catabolic enzyme, dihydropyrimidine dehydrogenase (DPD), has been shown to be responsible for a pharmacogenetic syndrome in which administration of 5-fluorouracil is associated with severe and potentially life-threatening toxicity. Following the recent availability of the cDNA for DPD, there were initial reports of several molecular defects (point mutations, deletio...

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism. Ethynyluracil (776C) is a very potent, mechanism-based irreversible DPD inhibitor that improves the antitumor efficacy and the therapeutic index of FU in laboratory animals. We tested the cytotoxic effects of the FU-776C combination on a panel of 12 human cancer cell lines (4 breast, 4 head and ...

Biochemical modulation of 5-fluorouracil (5-FU) has been used over the past 20 years to improve the therapeutic efficacy of this antineoplastic agent. Recently, modulation of the catabolic pathway of this fluoropyrimidine has been the focus of extensive preclinical and clinical investigation. Dihydropyrimidine dehydrogenase catalyzes the rate-limiting step in the catabolism of 5-FU and rapidly ...

To the Editor: In their important article, Ezzeldin et al. (1) report a positive association between dihydropyrimidine dehydrogenase (DPD) deficiency and the DPD gene (DPYD) promoter hypermethylation in peripheral blood mononuclear cells of studied individuals. The authors focused on methylation in the individuals with the DPD deficiency, but did not elaborate on the impact of hypermethylation ...

Dihydropyrimidine dehydrogenase (DPDase) catalyzed the debromination of 5-bromo-5,6-dihydrouracil (BrUH2) to uracil at pH 7.7 and 37 degrees C. The debrominating activity of DPDase was increased 5-fold by treatment with H2O2, whereas the dehydrogenating activity was inhibited by this treatment. The time course for increasing the debrominating activity by H2O2 was similar to that for decreasing ...