UFT and its metabolites inhibit cancer-induced angiogenesis - Via a VEGF-related pathway

Treatment with UFT for spontaneous lung metastasis of murine renal carcinom a (RENCA) after resection of the primary tumor has resulted in significant prolongation of the life span of tumor-bearing animals. UFT inhibited the g rowth of metastatic nodules in the lung, apparently via decreased density o f microvessels irt the metastatic foci. Subsequent experiments used dorsal air sac assay to directly trace newly forming microvessels. UFT abrogated t he process of angiogenesis, induced by the RENCA cells, in a dose-dependent manner. The inhibitory effect appeared to originate from tegafur, a compon ent of UFT, and from its known metabolites:fluorouracil (5-FU), gamma -hydr oxybutyric acid (GHB) and gamma -butyrolactone (GBL). The inhibition of ang iogenesis by UFT appeared to be a common phenomenon, also observed in other human cancer cell lines characterized by an excessive production of vascul ar endothelial growth factor (VEGF)-such as gastric, lung, and colon cancer s, In vitro analysis revealed that 5-FU and gamma -hydroxybutyric acid regu lated VEGF-dependent responses of human umbilical vein endothelial cells, D orsal air sac assay revealed that UFT, 5-FU, and gamma -hydroxybutyric acid strongly inhibited the angiogenesis induced by recombinant human VEGF, The se data suggest that the antiangiogenic activity of UFT is at least partial ly associated with an ability of the metabolites of UFT to interfere with V EGF-dependent responses of vascular endothelial cells.