A Possible Cause and Remedy for the Clinical Failure of 5-Fluorouracil Plus Eniluracil

Abstract

Eniluracil is a potent inactivator of dihydropyrimidine dehydrogenase (uracil reductase), the enzyme that rapidly catabolizes 5-fluorouracil (5-FU). Although eniluracil in combination with 5-FU was promising in phase I and II studies, in 2 multicenter phase III colorectal cancer studies, eniluracil dosed in a 10-to-1 ratio to 5-FU produced less antitumor benefit than the standard regimen of 5-FU/leucovorin without eniluracil. The current study tested whether the high eniluracil doses caused the clinical failure. The effect of excess eniluracil versus adequate eniluracil on 5-FU antitumor activity was studied in rats bearing large transplanted colon tumors. The rats were divided into 3 groups: group A received no treatment, group B was treated with eniluracil 1 mg/kg (adequate) 1 hour before 5 mg/kg 5-FU, and group C was treated identically to group B but also received eniluracil 25 mg/kg (excess) 5 minutes before 5-FU administration. The rate of complete tumor regression (cure) was 0% in group A (no treatment), 88% in group B (adequate eniluracil), and 25% in group C (excess eniluracil). Toxicity was minimal. Only slight weight loss occurred in all groups. When the eniluracil dose is in 5-fold excess to 5-FU (as in the phase III clinical trials), the antitumor activity of 5-FU was significantly diminished. Moreover, to maximize the antitumor activity of 5-FU, eniluracil must not be present in excess over 5-FU in rats bearing tumors. Simple strategies to achieve optimal antitumor efficacy are presented.