Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling.
Interaction between vascular endothelial growth factor (VEGF) and its cognate receptors, KDR/Flk-1 and Flt-1, of vascular endothelial cells is expected to induce an angiogenesis "switch" in tumors and other angiogenesis-associated diseases. SU5416, a selective inhibitor of the KDR/Flk-1 tyrosine kinase, is known to be a potent inhibitor of tumor angiogenesis. In this study, we first observed that SU5416 inhibited Flt-1 tyrosine kinase activity at similar doses, in addition to inhibiting KDR/Flk-1 tyrosine kinase activity in response to VEGF. SU5416 inhibited cell migration of human vascular endothelial cells expressing both Flt-1 and KDR in response to VEGF and also inhibited the cell migration in response to placenta growth factor (PIGF), a specific ligand for Flt-1. Chemotaxis of monocytes expressing only Flt-1 was also inhibited by SU5416 in a dose-dependent manner. Moreover, SU5416 was found to inhibit tyrosine kinase of Flt-1 in response to PIGF in vitro. And angiogenesis induced by PIGF in a Matrigel plug assay was inhibited by administration of SU5416. The antiangiogenic effects by this VEGF receptor- targeting compound appeared to be mediated through interference not only with KDR/Flk-1 but also with Flt-1. Cell migration of vascular endothelial cells and monocytic cells through Flt-1, thus, might play a key role in VEGF- induced tumor angiogenesis in concert with KDR/Flk-1.[1]References
- Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. Itokawa, T., Nokihara, H., Nishioka, Y., Sone, S., Iwamoto, Y., Yamada, Y., Cherrington, J., McMahon, G., Shibuya, M., Kuwano, M., Ono, M. Mol. Cancer Ther. (2002) [Pubmed]
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