alpha-fluoro-beta-alanine: Effects on the antitumor activity and toxicity of 5-fluorouracil

We have shown previously that (R)-5-fluoro-5,6 dihydrouracil (FUraH(2)) att enuates the antitumor activity of 5 fluorouracil (FUra) in rats bearing adv anced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alan ine (FBAL), the predominant catabolite of FUra that is formed rapidly via F UraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5-ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil treated mice bearing MOPC-315 mye loma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also eva luated the effect of thymidylate synthase (TS) and thymidine kinase (TK) fr om tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activit y of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition (similar to 35%) at 18 hr. However, si gnificantly more TS inhibition was observed in the Eniluracil/FUra group th an in the FUra-alone group at 120 hr. FBAL did not alter the effect of Enil uracil/FUra in TS inhibition. Neither EUraH(2) nor FBAL affected the IC50 o f FUra in culture. Thus, the effect of FBAL did not result from direct comp etition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the e ffect requires the complexity of a living organism or an established tumor. (C) 2000 Elsevier Science Inc.