UFT and Its Metabolites Inhibit the Angiogenesis Induced by Murine Renal Cell Carcinoma, as Determined by a Dorsal Air Sac Assay in Mice

• Published in: Clinical cancer research Vol. 5; no. 8; pp. 2185 - 2191
• Main Authors: YONEKURA, K, BASAKI, Y, CHIKAHISA, L, OKABE, S, HASHIMOTO, A, MIYADERA, K, WIERZBA, K, YAMADA, Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.1999
• Subjects: 4-Butyrolactone - therapeutic use; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Carcinoma, Renal Cell - blood supply; Cell Division - drug effects; Chemotherapy; Diffusion Chambers, Culture; Dose-Response Relationship, Drug; Floxuridine - therapeutic use; Fluorouracil - therapeutic use; Hydroxybutyrates - therapeutic use; Kidney Neoplasms - blood supply; Male; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Tegafur - therapeutic use; Tumor Cells, Cultured; Uracil - therapeutic use; Antineoplastic agent; Carcinoma; Back (anatomy); Metabolite; Toxicity; Tegafur; Kidney; Angiogenesis; Established cell line; Neovascularization; Tumor cell; Fluorouracil; Kidney disease; Urinary system disease; Doxifluridine; Treatment efficiency; Fluoropyrimidine derivatives; Rodentia; Air sac; Antimetastatic agent; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Pyrimidine derivatives; Uracil
• ISSN: 1078-0432; 1557-3265

UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer 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 assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice. In this model, UFT showed a strong angiogenesis-inhibitory 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. Moreover, we have found that γ-hydroxybutyric acid and γ-butyrolactone, the metabolites of FT, possess a potent angiogenesis inhibitory effect that is amplified when the compounds are administered by a continuous infusion. This may reflect a transition in blood concentration of each metabolite resulting from the administration of UFT. Similar results were also obtained with respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-inhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and long-lasting blood levels of 5-FU and partly due the inhibitory effects derived from γ-hydroxybutyric acid and γ-butyrolactone, UFT-specific metabolites.