Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib ("Iressa', ZD1839)
Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib ("Iressa', ZD1839)
复制标题
DOI：
10.1111/j.1349-7006.2004.tb02496.x
复制
发表时间：
2004-07-01
期刊：
影响因子：
5.7
通讯作者：
Ono, M
中科院分区：
文献类型：
--
作者：
Hirata, A;Uehara, H;Ono, M
靶向EGFR酪氨酸激酶的吉非替尼（“Iressa”，ZD 1839）的开发是最近的治疗亮点。我们已经报道，吉非替尼是抗血管生成在体外，以及在体内。在这项研究中，我们询问了吉非替尼的抗血管生成作用是否是由于EGF对血管内皮细胞活化的直接作用。EGF以及VEGF在小鼠角膜的无血管区域中引起明显的血管生成，并且吉非替尼的腹膜内给药几乎完全阻断了对EGF的反应，但对VEGF没有。免疫组化分析表明，EGFR的EGF在新生血管的磷酸化，和吉非替尼显着减少这种影响。吉非替尼还通过EGFR抑制培养的微血管内皮（HMVE）细胞中ERK 1/2的下游激活。这些发现表明，吉非替尼在新生血管的血管内皮细胞中的抗血管生成作用部分归因于直接抑制EGFR活化，并且恶性肿瘤中的内皮细胞在吉非替尼的癌症治疗功效中起关键作用。
The development of gefitinib ('Iressa', ZD1839) by targeting the EGFR tyrosine kinase is a recent therapeutic highlight. We have reported that gefitinib is antiangiogenic in vitro, as well as in vivo. In this study, we asked if the anti-angiogenic action of gefitinib is due to a direct effect on activation of vascular endothelial cells by EGF. EGF, as well as VEGF, caused pronounced angiogenesis in an avascular area of the mouse cornea, and i.p. administration of gefitinib almost completely blocked the response to EGF, but not to VEGF. Immunohistochemical analysis demonstrated phosphorylation of EGFR by EGF in the neovasculature, and gefitinib markedly reduced this effect. Gefitinib also inhibited downstream activation of ERK 1/2 via EGFR in cultured microvascular endothelial (HMVE) cells. These findings suggest that the anti-angiogenic effect of gefitinib in the vascular endothelial cells of neo-vasculature is partly attributable to direct inhibition of EGFR activation, and that endothelial cells in malignant tumors play a critical role in the cancer therapeutic efficacy of gefitinib.