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

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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.

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Authors and Affiliations

  1. Glaxo Wellcome, Inc, Research Triangle Park, NC, USA

    Melanie T. Paff, David P. Baccanari, Stephen T. Davis & Robert L. Tansik

  2. Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY, USA

    Shousong Cao & Youcef M. Rustum

  3. Spector Consulting Services, Durham, NC, USA

    Thomas Spector

Authors
  1. Melanie T. Paff
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  2. David P. Baccanari
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  6. Youcef M. Rustum
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  7. Thomas Spector
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Paff, M.T., Baccanari, D.P., Davis, S.T. et al. Preclinical Development of Eniluracil: Enhancing the Therapeutic Index and Dosing Convenience of 5-Fluorouracil. Invest New Drugs 18, 365–371 (2000). https://doi.org/10.1023/A:1006401432488

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