title: Preclinical development of eniluracil: enhancing the therapeutic index and dosing convenience of 5-fluorouracil.
abstract: 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 dehydrogenase (DPD), the first enzyme in the catabolic pathway of 5-FU. By temporarily eliminating this prevalent enzyme, eniluracil provides predictable dosing of 5-FU and enables oral administration of 5-FU to replace intravenous bolus 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 catabolites. Most importantly, in laboratory animals, eniluracil increases the therapeutic index and absolute efficacy of 5-FU. Accompanying reports in this journal indicate that eniluracil has promising clinical potential.
authors.affiliation: Glaxo Wellcome, Inc, Research Triangle Park, NC 27709, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Paff
authors.forename: D P
authors.initials: DP
authors.lastname: Baccanari
authors.forename: S T
authors.initials: ST
authors.lastname: Davis
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.forename: R L
authors.initials: RL
authors.lastname: Tansik
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
authors.forename: T
authors.initials: T
authors.lastname: Spector
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D042943:Dihydrouracil Dehydrogenase (NADP); D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil