We have shown previously that
(R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of
5-fluorouracil (FUra) in rats bearing advanced
colorectal carcinoma. Presently, we found that
alpha-fluoro-beta-alanine (
FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(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 myeloma 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 evaluated the effect of
thymidylate synthase (TS) and
thymidine kinase (TK) from
tumor extracts after FUra +/-
Eniluracil +/-
FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the
Eniluracil/FUra group than in the FUra-alone group at 120 hr.
FBAL did not alter the effect of
Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor
FBAL affected the IC(50) of FUra in culture. Thus, the effect of
FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established
tumor.