title: VGA1155, a novel binding antagonist of VEGF, inhibits angiogenesis in vitro and in vivo.
abstract: The process of angiogenesis involves the formation of new blood vessels from established vasculature and is essential for progressive tumor growth and metastasis. Since vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis, it is reasonable to expect that antagonizing VEGF binding to its receptor may be effective in cancer therapy. Our previous study found that a novel low molecular weight compound, VGA1155, inhibited binding between radioisotope-labelled VEGF and cells overexpressing its two receptors, Flt-1 and KDR/Flk-1, that is, NIH3T3-Flt-1 and NIH3T3-KDR, respectively. In the present study, we investigated the anti-angiogenic effects of VGA1155 based on VEGF inhibition. VGA1155 inhibited VEGF-induced DNA synthesis of human umbilical vein endothelial cells (HUVEC) and human retinal endothelial cells (HREC) in a concentration-dependent manner. VGA1155 also inhibited VEGF-induced tube formation of HUVEC in vitro and tumor angiogenesis toward B16-BL6 melanoma after orthotopic implantation into the skin of the back. On the other hand, VGA 1155 did not affect the proliferation of human epidermoid carcinoma (KB) cells and mouse mammary carcinoma (MM2) cells. It also had no effect on the activity of several cytosolic kinases such as p55fyn and p56lck. These findings suggest that VGA1155 inhibits endothelial cell growth and angiogenesis by inhibiting VEGF function but not non-specific cytotoxicity. VGA1155 thus exhibits promise as an antiangiogenic or anti-tumor agent with fewer side-effects.
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, 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: Hisao
authors.initials: H
authors.lastname: Ikeya
authors.forename: Noriko
authors.initials: N
authors.lastname: Hirayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Itokawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Aozuka
authors.forename: Kazunori
authors.initials: K
authors.lastname: Samata
authors.forename: Shiro
authors.initials: S
authors.lastname: Nakaike
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013936:Thymidine / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D001565:Benzoates; C487956:VGA1155; D042461:Vascular Endothelial Growth Factor A; D013936:Thymidine