Investigational New Drugs

, Volume 18, Issue 4, pp 365-371

First online:

Preclinical Development of Eniluracil: Enhancing the Therapeutic Index and Dosing Convenience of 5-Fluorouracil

  • Melanie T. PaffAffiliated withGlaxo Wellcome, Inc
  • , David P. BaccanariAffiliated withGlaxo Wellcome, Inc
  • , Stephen T. DavisAffiliated withGlaxo Wellcome, Inc
  • , Shousong CaoAffiliated withGrace Cancer Drug Center, Roswell Park Cancer Institute
  • , Robert L. TansikAffiliated withGlaxo Wellcome, Inc
  • , Youcef M. RustumAffiliated withGrace Cancer Drug Center, Roswell Park Cancer Institute
  • , Thomas SpectorAffiliated withSpector Consulting Services

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Eniluracil (5-ethynyluracil, GW 776, 776C85) isbeing developed as a novel modulator of 5-fluorouracil (5-FU) forthe treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), thefirst enzyme in the catabolic pathway of 5-FU. By temporarilyeliminating this prevalent enzyme, eniluracil providespredictable dosing of 5-FU and enables oral administration of5-FU to replace intravenous bolus and continuously infuseddosing. New DPD is synthesized with a half-life of 2.6 days. Italso eliminates the formation of problematic 5-FU catabolites.Most importantly, in laboratory animals, eniluracil increases thetherapeutic index and absolute efficacy of 5-FU. Accompanyingreports in this journal indicate that eniluracil has promisingclinical potential.

cancer dihydropyrimidine dehydrogenase GW 776 oral dosing uracil reductase 776C85