title: YM-231146, a novel orally bioavailable inhibitor of vascular endothelial growth factor receptor-2, is effective against paclitaxel resistant tumors.
abstract: Chemotherapy using anticancer drugs induces serious the problem of multidrug resistance (MDR) in the cancer cells. In contrast, endothelial cells so rarely acquire MDR that antiangiogenesis therapy has recently been considered as an effective means for cancer chemotherapy. We screened compounds in the chemical library to find a novel and orally active antitumor agent with vascular endothelial growth factor receptor-2 tyrosine kinase (VEGF-R2 TK) inhibition. The result was YM-231146 (IC50=0.080 microM). YM-231146 inhibited VEGF-stimulated proliferation, VEGF-R2 autophosphorylation, and vessel sprout formation of human vascular endothelial cells at concentrations between 0.15-0.30 microM. However, YM-231146 did not inhibit cancer cell proliferation at these concentrations (IC50>5 microM). In the in vivo studies, once-daily oral dosing of YM-231146 to human cancer xenografts elicited antitumor activity at doses of 3-100 mg/kg. Moreover, YM-231146 completely inhibited tumor growth of paclitaxel-resistant cancer cells without decreasing body weight at a dose of 100 mg/kg. These results suggest that YM-231146 is a novel orally bioavailable inhibitor of VEGF-R2 that would be useful for the treatment of multidrug resistant tumors.
authors.affiliation: Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 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: Kenna
authors.initials: K
authors.lastname: Shirasuna
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kudoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D009025:Morpholines; D011804:Quinolines; C506332:YM-231146; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel