論文 - 詳細
| RRC ID | 68713 |
|---|---|
| 著者 | Awazu Y, Mizutani A, Nagase Y, Tsuchiya S, Nakamura K, Kakoi Y, Kitahara O, Takeuchi T, Yamasaki S, Miyamoto N, Iwata H, Miki H, Imamura S, Hori A. |
| タイトル | Anti-angiogenic and anti-tumor effects of TAK-593, a potent and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase. |
| ジャーナル | Cancer Sci |
| Abstract |
We recently reported that TAK-593, a novel imidazo[1,2-b]pyridazine derivative, is a highly potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor tyrosine kinase families. Moreover, TAK-593 exhibits a uniquely long-acting inhibitory profile towards VEGF receptor 2 (VEGFR2) and PDGF receptor β (PDGFRβ). In this study, we demonstrated that TAK-593 potently inhibits VEGF- and PDGF-stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells. TAK-593 also potently inhibits VEGF-induced tube formation of endothelial cells co-cultured with fibroblasts. Oral administration of TAK-593 exhibited strong anti-tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure. Even after the blood and tissue concentrations of TAK-593 decreased below the detectable limit, a pharmacodynamic marker (phospho VEGFR2) was almost completely suppressed, indicating that its long duration of enzyme inhibition might contribute to the potent activity of TAK-593. Immunohistochemical staining indicated that TAK-593 showed anti-proliferative and pro-apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo. Furthermore, dynamic contrast-enhanced magnetic resonance imaging revealed that TAK-593 reduced tumor vessel permeability prior to the onset of anti-tumor activity. In conclusion, TAK-593 is an extremely potent VEGFR/PDGFR kinase inhibitor whose potent anti-angiogenic activity suggests therapeutic potential for the treatment of solid tumors. |
| 巻・号 | 104(4) |
| ページ | 486-94 |
| 公開日 | 2013-4-1 |
| DOI | 10.1111/cas.12101 |
| PMID | 23305239 |
| PMC | PMC7657107 |
| MeSH | Angiogenesis Inhibitors / therapeutic use* Animals Antineoplastic Agents / therapeutic use* Apoptosis / drug effects Azabicyclo Compounds / pharmacology Azabicyclo Compounds / therapeutic use* Capillary Permeability / drug effects Cell Proliferation / drug effects Humans Mice Mice, Nude Mice, SCID Neoplasms / blood supply Neoplasms / drug therapy* Neovascularization, Pathologic / drug therapy Pyrazoles / pharmacology Pyrazoles / therapeutic use* Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors* Vascular Endothelial Growth Factor A / antagonists & inhibitors* Xenograft Model Antitumor Assays |
| IF | 4.966 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MKN45(RCB1001) |