Investigational New Drugs

, Volume 18, Issue 4, pp 365–371 | Cite as

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

  • Melanie T. Paff
  • David P. Baccanari
  • Stephen T. Davis
  • Shousong Cao
  • Robert L. Tansik
  • Youcef M. Rustum
  • Thomas Spector
Article

Abstract

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 

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Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Melanie T. Paff
    • 1
  • David P. Baccanari
    • 1
  • Stephen T. Davis
    • 1
  • Shousong Cao
    • 2
  • Robert L. Tansik
    • 1
  • Youcef M. Rustum
    • 2
  • Thomas Spector
    • 3
  1. 1.Glaxo Wellcome, IncUSA
  2. 2.Grace Cancer Drug CenterRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Spector Consulting ServicesDurhamUSA

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