UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice

UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a m olar ratio of 1:4, is widely used in clinical practice in Japan to treat ca ncer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac a ssay. Marked angiogenesis is induced by implantation of a chamber containin g RENCA cells into mice. In this model, UFT showed a strong angiogenesis-in hibitory effect, whereas 5-fluorouracil (5-FU) and doxifluridine were less effective, Additional experiments revealed FT to be effective component of UFT; uracil remained ineffective in the inhibition of angiogenesis, Moreove r, we have found that gamma-hydroxybutyric acid and gamma-butyrolactone, th e metabolites of FT, possess a potent angiogenesis inhibitory effect that i s amplified when the compounds are administered by a continuous infusion. T his may reflect a transition in blood concentration of each metabolite resu lting from the administration of UFT, Similar results were also obtained wi th respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-i nhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and longl asting blood levels of 5-FU and partly due the inhibitory effects derived f rom gamma-hydroxybutyric acid and gamma-butyrolactone, UFT-specific metabol ites.