Journal article
Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil
Cancer research (Chicago, Ill.), Vol.55(6), pp.1239-1241
01/01/1995
PMID: 7882316
Abstract
5-Ethynyluracil (5-EU; 776C85) is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase that improves the antitumor activity of 5-fluorouracil (5-FU) to a greater extent than can be accounted for by the improved 5-FU pharmacokinetics that result from preventing the catabolism of 5-FU. We therefore tested the effects of (R)-5-fluoro-5,6-dihydrouracil (5-FUH sub(2)), the 5-FU catabolite extensively formed in the absence of 5-EU, on the antitumor activity and toxicity of 5-FU in 5-EU-treated rats bearing large s.c. tumors. Rats were dosed once weekly for 3 weeks with the following regimens: 100 mg/kg 5-FU (maximum tolerated dose), 10 mg/kg 5-FU 1 h after 1 mg/kg 5-EU, or 10 mg/kg 5-FU plus 90 mg/kg 5-FUH sub(2) 1 h after 1 mg/kg 5-EU. The latter regimen was designed to approximate the exposure produced from 5-FU in the absence of 5-EU, where >80% of the dose is catabolized. 5-FU produced complete and sustained tumor regressions in 94% of the animals pretreated with 5-EU. In contrast, 5-FU in combination with 5-FUH sub(2) produced complete regression in only 38% of the 5-EU-treated rats, which was similar to the antitumor activity of 5-FU in the absence of 5-EU. All treatments resulted in 7-11% transient weight loss. 5-FU produced no other notable toxicity in 5-EU-treated rats. However, 5-FUH sub(2) added to this regimen caused transient diarrhea and stomatitis in 13% of the animals, which was similar to the toxicity produced by 5-FU in the absence of 5-EU. Thus, 5-FUH sub(2), or other downstream catabolites of 5-FU, impaired the antitumor activity and slightly increased the toxicity of 5-FU. Accordingly, 5-EU appeared to improve the efficacy of 5-FU by preventing the formation of 5-FU catabolites.
Details
- Title: Subtitle
- Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil
- Creators
- T SpectorS CaoY RustumJ A HarringtonDJT Porter
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.55(6), pp.1239-1241
- PMID
- 7882316
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 01/01/1995
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359906902771
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