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)) 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.
Cao
S
S
Department of Pharmacology, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY, USA. scao@sc3101.med.buffalo.edu
Baccanari
D P
DP
Rustum
Y M
YM
Davis
S T
ST
Tansik
R L
RL
Porter
D J
DJ
Spector
T
T
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine; D005472:Fluorouracil