title: gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor.
abstract: UFT, a drug composed of uracil and tegafur at the molar ratio of 4:1, is an orally active agent for the treatment of a wide variety of malignant tumours. Using a murine dorsal air sac (DAS) assay, we have previously shown that UFT and its metabolites, gamma-hydroxybutyric acid (GHB) and 5-fluorouracil (5-FU), inhibited the angiogenesis induced by murine renal cell carcinoma. Here we report that UFT was more effective than other fluorinated pyrimidines such as 5-FU and doxifluridine (5'-DFUR) in blocking the angiogenic responses elicited by five human cancer cell lines which produced high levels of vascular endothelial growth factor (VEGF), but no detectable fibroblast growth factor-2 (FGF-2) in vitro. In contrast, UFT was unable to block the angiogenic response to one human gastric cancer cell line which produced both VEGF and FGF-2 in vitro. However, the production or secretion of VEGF by these cells was unaffected by GHB and 5-FU treatment. Interestingly, GHB suppressed the chemotactic migration and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF, without inhibiting their DNA synthesis. Since GHB did not affect the FGF-2-driven activities in HUVECs, its action appears to be VEGF-selective. On the other hand, 5-FU inhibited DNA synthesis and migration of HUVECs stimulated by both VEGF and FGF-2, and tube formation driven by VEGF, suggesting that 5-FU is cytotoxic to endothelial cells. The inhibitory effects of 5-FU, and especially those GHB, were reproduced under in vivo condition using the DAS assay. The VEGF-mediated angiogenesis was significantly inhibited by UFT, 5-FU, and especially by GHB. We propose that the selective inhibitory effects of GHB on VEGF-mediated responses of endothelial cells are involved in the anti-angiogenic activity of UFT.
authors.affiliation: Cancer Research Laboratory, Taiho Pharmaceutical Co., Ltd, Hanno City, Saitama, Japan. y-basaki@taiho.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Basaki
authors.forename: L
authors.initials: L
authors.lastname: Chikahisa
authors.forename: K
authors.initials: K
authors.lastname: Aoyagi
authors.forename: K
authors.initials: K
authors.lastname: Miyadera
authors.forename: K
authors.initials: K
authors.lastname: Yonekura
authors.forename: A
authors.initials: A
authors.lastname: Hashimoto
authors.forename: S
authors.initials: S
authors.lastname: Okabe
authors.forename: K
authors.initials: K
authors.lastname: Wierzba
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005467:Floxuridine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011355:Prodrugs / Q000493:pharmacokinetics*; D019736:Prostheses and Implants; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012978:Sodium Oxybate / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D005641:Tegafur / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014498:Uracil / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; D011355:Prodrugs; D011994:Recombinant Proteins; C096910:UFT(R) drug; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005467:Floxuridine; D016222:Fibroblast Growth Factor 2; D005641:Tegafur; D014498:Uracil; D012978:Sodium Oxybate; D005472:Fluorouracil; C025034:doxifluridine