Preclinical development of eniluracil: enhancing the therapeutic index and dosing 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 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.
Paff
M T
MT
Glaxo Wellcome, Inc, Research Triangle Park, NC 27709, USA.
Baccanari
D P
DP
Davis
S T
ST
Cao
S
S
Tansik
R L
RL
Rustum
Y M
YM
Spector
T
T
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*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil