Itokawa Takashi, Nokihara Hiroki, Nishioka Yasuhiko, Sone Saburo, Iwamoto Yukihide, Yamada Yuji, Cherrington Julie, McMahon Gerald, Shibuya Masabumi, Kuwano Michihiko, Ono Mayumi
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Mol Cancer Ther. 2002 Mar;1(5):295-302.
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.
血管内皮生长因子（VEGF）与其血管内皮细胞的同源受体KDR/Flk-1和Flt-1之间的相互作用有望在肿瘤及其他血管生成相关疾病中引发血管生成“开关”。SU5416是一种KDR/Flk-1酪氨酸激酶的选择性抑制剂，已知是一种有效的肿瘤血管生成抑制剂。在本研究中，我们首先观察到，SU5416除了抑制VEGF刺激下的KDR/Flk-1酪氨酸激酶活性外，在相似剂量下还抑制Flt-1酪氨酸激酶活性。SU5416抑制表达Flt-1和KDR的人血管内皮细胞对VEGF的细胞迁移，也抑制其对Flt-1的特异性配体胎盘生长因子（PIGF）的细胞迁移。仅表达Flt-1的单核细胞的趋化性也被SU5416以剂量依赖性方式抑制。此外，发现SU5416在体外抑制Flt-1对PIGF的酪氨酸激酶活性。在基质胶植入实验中，SU5416给药可抑制PIGF诱导的血管生成。这种靶向VEGF受体的化合物的抗血管生成作用似乎不仅通过干扰KDR/Flk-1，还通过干扰Flt-1介导。因此，血管内皮细胞和单核细胞通过Flt-1的细胞迁移可能与KDR/Flk-1协同在VEGF诱导的肿瘤血管生成中起关键作用。
