title: YM-201627: an orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation.
abstract: We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC50s of 0.0039-0.12 microM), that would not be expected to have any direct antiproliferative effect on other cell types. YM-201627 inhibited angiogenesis in vitro at a concentration of 0.01 microM. In the in vivo studies, it inhibited microvessel formation induced by human melanoma A375 cells suspended in Matrigel (86% with twice-daily doses of 30 mg/kg). Moreover, once-daily oral dosing of YM-201627 to mice bearing A375 xenografts elicited significant antitumor activity (73% with daily doses of 10 mg/kg). These results suggest that YM-201627 is a selective growth inhibitor of endothelial cells, which may be useful for treatment of solid tumors.
authors.affiliation: Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. nobuaki.amino@jp.astellas.com
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Amino
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Ideyama
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamano
authors.forename: Sadao
authors.initials: S
authors.lastname: Kuromitsu
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tajinda
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Samizu
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kudoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000284:Administration, Oral; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D007093:Imidazoles; C512723:YM-201627; D040301:Vascular Endothelial Growth Factor Receptor-2