Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors.
Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors.
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发表时间：
1999-10
期刊：
影响因子：
11.2
通讯作者：
M. Prewett;James Huber;L. Yiwen;Angel Santiago;W. O'Connor;K. King;J. Overholser;A. Hooper;B. Pytowski;L. Witte;P. Bőhlen;D. Hicklin
中科院分区：
文献类型：
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作者：
M. Prewett;James Huber;L. Yiwen;Angel Santiago;W. O'Connor;K. King;J. Overholser;A. Hooper;B. Pytowski;L. Witte;P. Bőhlen;D. Hicklin
肿瘤血管生成是由肿瘤分泌的血管生成生长因子介导的，这些生长因子与其内皮细胞上表达的表面受体相互作用。血管内皮生长因子（VEGF）及其受体[胎肝激酶1（Flk-1）/含有激酶插入结构域的受体]在血管通透性和肿瘤血管生成中发挥重要作用。此前，我们报道了含有抗 Flk-1 和抗激酶插入结构域的受体单克隆抗体 (mAb) 的开发，该抗体可有效抑制 VEGF 结合和受体信号传导。在这里，我们报告了抗 Flk-1 mAb (DC101) 对血管生成和肿瘤生长的影响。在 C57BL/6 小鼠中使用补充生长因子（碱性成纤维细胞生长因子 + VEGF）基质胶塞和藻酸盐封装肿瘤细胞（路易斯肺）测定法检查体内血管生成。每 3 天全身给予 DC101 可以剂量依赖性方式显着减少基质胶塞和含肿瘤藻酸盐珠的新血管形成。基质胶塞的组织学分析显示内皮细胞和血管结构数量减少。使用几种小鼠肿瘤和无胸腺小鼠的人类肿瘤异种移植物来检查抗 Flk-1 mAb 治疗对肿瘤血管生成和生长的影响。抗 Flk-1 mAb 治疗显着抑制原发性小鼠 Lewis 肺肿瘤、4T1 乳腺肿瘤和 B16 黑色素瘤的生长以及 Lewis 肺转移瘤的生长。 DC101 还完全抑制已建立的表皮样瘤、胶质母细胞瘤、胰腺和肾人类肿瘤异种移植物的生长。抗 Flk-1 mAb 处理的肿瘤的组织学检查显示微血管密度降低、肿瘤细胞凋亡、肿瘤细胞增殖减少和广泛的肿瘤坏死。这些发现支持抗Flk-1 mAb治疗通过抑制肿瘤诱导的新血管形成来抑制肿瘤生长的结论，并证明抗VEGF受体抗体在治疗血管生成依赖性肿瘤中的治疗应用潜力。
Tumor angiogenesis is mediated by tumor-secreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor [fetal liver kinase 1 (Flk-1)/kinase insert domain-containing receptor] play an important role in vascular permeability and tumor angiogenesis. Previously, we reported on the development of anti-Flk-1 and antikinase insert domain-containing receptor monoclonal antibodies (mAbs) that potently inhibit VEGF binding and receptor signaling. Here, we report the effect of anti-Flk-1 mAb (DC101) on angiogenesis and tumor growth. Angiogenesis in vivo was examined using a growth factor supplemented (basic fibroblast growth factor + VEGF) Matrigel plug and an alginate-encapsulated tumor cell (Lewis lung) assay in C57BL/6 mice. Systemic administration of DC101 every 3 days markedly reduced neovascularization of Matrigel plugs and tumor-containing alginate beads in a dose-dependent fashion. Histological analysis of Matrigel plugs showed reduced numbers of endothelial cells and vessel structures. Several mouse tumors and human tumor xenografts in athymic mice were used to examine the effect of anti-Flk-1 mAb treatment on tumor angiogenesis and growth. Anti-Flk-1 mAb treatment significantly suppressed the growth of primary murine Lewis lung, 4T1 mammary, and B16 melanoma tumors and growth of Lewis lung metastases. DC101 also completely inhibited the growth of established epidermoid, glioblastoma, pancreatic, and renal human tumor xenografts. Histological examination of anti-Flk-1 mAb-treated tumors showed evidence of decreased microvessel density, tumor cell apoptosis, decreased tumor cell proliferation, and extensive tumor necrosis. These findings support the conclusion that anti-Flk-1 mAb treatment inhibits tumor growth by suppression of tumor-induced neovascularization and demonstrate the potential for therapeutic application of anti-VEGF receptor antibody in the treatment of angiogenesis-dependent tumors.