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
|
リソース情報 |
ヒト・動物細胞 |
MKN45(RCB1001) |