title: A novel low molecular weight VEGF receptor-binding antagonist, VGA1102, inhibits the function of VEGF and in vivo tumor growth.
abstract: Vascular endothelial cell growth factor (VEGF) plays an important role in the processes of angiogenesis. Angiogenesis appears to be essential for the growth of solid tumors and their metastasis. VEGF plays a principal role in tumor angiogenesis. To identify a compound that inhibits the binding of VEGF to its receptor, we used a high-throughput screening method and found that oxydibenzoic acid derivatives inhibited VEGF binding to its receptors. Among the active compounds, 5-[3-[4-(octadecyloxy)phenyl]propionylamino]-2,4'-oxydibenzoic acid (VGA1102) was selected based on its potent binding inhibitory activity. VGA1102 inhibited [(125)I]VEGF binding to both of two VEGF receptor-transfected cell lines, NIH-Flt-1 and NIH-KDR/Flk-1, in a concentration-dependent manner, with IC(50) values of 0.66+/-0.07 and 0.61+/-0.16 micro M, respectively. VGA1102 (10 micro M) exhibited inhibitory activity against VEGF-induced receptor autophosphorylation. VGA1102 also inhibited VEGF-induced growth of rat liver sinusoidal endothelial cells (IC(50)=0.89+/-0.16 micro M) as well as VEGF-induced tube formation of HUVEC in vitro. VGA1102 reduced intradermal VEGF-induced vascular permeability in guinea pigs. Treatment with VGA1102 (50 mg/kg, i.p., days 0-20) significantly increased the lifespan of MM2-bearing mice with an increase in lifespan of >195.8%, and all such mice were long-term survivors on day 71. Furthermore, VGA1102 (50 mg/kg, i.p.) administered daily suppressed the growth of nude mice transplanted with LC-6 human non-small-cell lung cancer. These results suggest that VGA1102 inhibits VEGF function resulting in inhibition of tumor angiogenesis, which led to suppression of growth of human tumors transplanted into nude mice.
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, 331-9530 Saitama, Japan. y.ueda@po.rd.taisho.co.jp
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Ueda
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamagishi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Samata
authors.forename: Hisao
authors.initials: H
authors.lastname: Ikeya
authors.forename: Noriko
authors.initials: N
authors.lastname: Hirayama
authors.forename: Tadayasu
authors.initials: T
authors.lastname: Okazaki
authors.forename: Sumi
authors.initials: S
authors.lastname: Nishihara
authors.forename: Koshi
authors.initials: K
authors.lastname: Arai
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Shiro
authors.initials: S
authors.lastname: Nakaike
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000473:Alkanes / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002199:Capillary Permeability; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D006168:Guinea Pigs; D007263:Infusions, Parenteral; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008970:Molecular Weight; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D051381:Rats; D017208:Rats, Wistar; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000502:physiology*
chemical_list: C487873:5-(3-(4-(octadecyloxy)phenyl)propionylamino)-2,4'-oxydibenzoic acid; D000473:Alkanes; D020533:Angiogenesis Inhibitors; D001565:Benzoates; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor