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The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile.
Fujita, Hidenori; Miyadera, Kazutaka; Kato, Masanori; Fujioka, Yayoi; Ochiiwa, Hiroaki; Huang, Jinhong; Ito, Kimihiro; Aoyagi, Yoshimi; Takenaka, Toru; Suzuki, Takamasa; Ito, Satoko; Hashimoto, Akihiro; Suefuji, Takashi; Egami, Kosuke; Kazuno, Hideki; Suda, Yoshimitsu; Nishio, Kazuto; Yonekura, Kazuhiko.
Afiliación
  • Fujita H; Corresponding Author: Hidenori Fujita, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. hide-fujita@taiho.co.jp.
Mol Cancer Ther ; 12(12): 2685-96, 2013 Dec.
Article en En | MEDLINE | ID: mdl-24140932
VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 µmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinolinas / Tiourea / Proteínas Proto-Oncogénicas c-met / Receptores de Factores de Crecimiento Endotelial Vascular / Inhibidores de Proteínas Quinasas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2013 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinolinas / Tiourea / Proteínas Proto-Oncogénicas c-met / Receptores de Factores de Crecimiento Endotelial Vascular / Inhibidores de Proteínas Quinasas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2013 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos