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Attenuation of the Antitumor Activity of 5-Fluorouracil by (R)-5-Fluoro-5,6-dihydrouracil

Division of Experimental Therapy, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709 [T. S., J. A. H., D. J. T. P.], and Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263 [S. C., Y. M. R.]

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-FUH₂), 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-FUH₂ 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-FUH₂ 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-FUH₂ 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-FUH₂, or other downstream catabolites of 5-FU, impaired the anti-tumor 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.

¹ To whom requests for reprints should be addressed.

Received 1/ 9/95. Accepted 2/ 2/95.

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