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 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 gamma-hydroxybutyric acid and gamma-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 gamma-hydroxybutyric acid and gamma-butyrolactone, UFT-specific metabolites.
Yonekura
K
K
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno-City, Saitama, Japan. yonekura@hanno.taiho.co.jp
Basaki
Y
Y
Chikahisa
L
L
Okabe
S
S
Hashimoto
A
A
Miyadera
K
K
Wierzba
K
K
Yamada
Y
Y
D015107:4-Butyrolactone / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply*; D002455:Cell Division / Q000187:drug effects; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D005467:Floxuridine / Q000627:therapeutic use; D005472:Fluorouracil / Q000627:therapeutic use; D006885:Hydroxybutyrates / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D005641:Tegafur / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000627:therapeutic use
D006885:Hydroxybutyrates; D005467:Floxuridine; D005641:Tegafur; C111420:4-hydroxybutyric acid; D014498:Uracil; D015107:4-Butyrolactone; D005472:Fluorouracil; C025034:doxifluridine