No circadian variation of dihydropyrimidine dehydrogenase, uridine phosphorylase, beta-alanine, and 5-fluorouracil during continuous infusion of 5-fluorouracil.

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases and it catalyses the reduction of thymine and uracil to 5,6-dihydrothymine and 5,6-dihydrouracil, respectively. In mammals, the degradation of uracil by DPD is the only pathway leading to the biosynthesis of β-alanine. Furthermore, DPD is also responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. 5FU is one of the few drugs that shows some antitumour activity against various otherwise untreatable tumours including carcinomas of the gastrointestinal tract, breast, ovary and skin. Furthermore, 5FU is one of the few drugs for which a limited clinical effect has been shown when applied as a single agent during the treatment of advanced colorectal cancer. In order to exert its cyto-toxic effect against cancer, 5FU must first be anabolised to the nucleotide level. 5FU can be converted into FUMP by a sequential, two-step reaction consisting of the initial addition of a ribose by uridine phosphorylase (UP) to yield 5-fluorouridine (5FUrd), followed by phos-phorylation to FUMP by uridine kinase. The direct conversion of 5FU to FUMP is catalyzed by orotate phosphoribosyl transferase (OPRT) which transfers the ribose-phosphate moiety from phosphoribosyl pyrophosphate (PRPP) to 5FU. Although the cytotoxic effects of 5FU are probably directly mediated by the anabolic pathways, the catabolic route plays a significant role since more than 80% of the administered 5FU is catabolised by DPD. It has been reported that the bioavailability, efficacy as well as host-toxicity of 5FU follows a circadian rhythm in rodents1 and cancer patients2. In the present study, we investigated whether a circadian variation could be observed of the activity of DPD, UP and the plasma concentration of β-alanine and 5FU in patients treated with continuous infusion of 5FU.