Preclinical development of eniluracil: Enhancing the therapeutic index anddosing convenience of 5-fluorouracil

Eniluracil (5-ethynyluracil, GW 776, 776C85) is being developed as a novel modulator of 5-fluorouracil (5-FU) for the treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogen ase (DPD), the first enzyme in the catabolic pathway of 5-FU. By temporaril y eliminating this prevalent enzyme, eniluracil provides predictable dosing of 5-FU and enables oral administration of 5-FU to replace intravenous bol us and continuously infused dosing. New DPD is synthesized with a half-life of 2.6 days. It also eliminates the formation of problematic 5-FU cataboli tes. Most importantly, in laboratory animals, eniluracil increases the ther apeutic index and absolute efficacy of 5-FU. Accompanying reports in this j ournal indicate that eniluracil has promising clinical potential.