Modulation of fluorouracil toxicity with uridine

The antineoplastic agent 5-fluorouracil (5-FU) is used in the treatment of various tumor types. However, its antitumor activity is limited. To be active, 5-FU has to be metabolized. Its mechanisms of action have been largely elucidated but are complex. Combining 5-FU with biochemical modulating agents that interfere with 5-FU metabolism may enhance its therapeutic index. Uridine is one of these biochemical modulating agents. The aim of combining 5-FU with uridine is that the latter will reduce the toxicity of 5-FU while its antitumor activity is retained. This will enable the use of higher 5-FU doses with a potential increased antitumor effect. The combination 5-FU/uridine has shown clear activity in preclinical models. However, application in the clinic is limited. From the preclinical experience, it seemed that high doses of uridine giving rise to prolonged exposure of uridine to the tissues would be required to achieve the biochemical effect. Thus, initial clinical studies investigated tolerance and toxicities of high-dose uridine in humans. Dose-limiting toxicity was fever. High-dose uridine given as intermittent intravenous infusions was feasible and reversed 5-FU-induced leukopenia. High-dose uridine led to millimolar plasma concentrations of uridine. However, its half life was short due to rapid catabolism. Oral administration of uridine has also been studied, but bioavailability was low. Further studies are required to define the role of uridine in the biochemical modulation of 5-FU activity.