E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor
E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor
复制标题
DOI：
10.1158/1535-7163.mct-10-0707
复制
发表时间：
2011-07-01
影响因子：
5.7
通讯作者：
Sone, Saburo
中科院分区：
文献类型：
--
作者：
Ogino, Hirokazu;Hanibuchi, Masaki;Sone, Saburo
虽然表皮生长因子受体（EGFR）酪氨酸激酶抑制剂改善了EGFR突变型肺癌患者的预后，但非突变型EGFR肺癌患者的预后，特别是转移性肺癌患者的预后仍然非常差。E7080是一种口服的多种酪氨酸激酶抑制剂，包括VEGF受体2 （VEGFR-2）和VEGFR-3，我们评估了E7080在无EGFR突变的肺癌细胞系的实验性多器官转移中的治疗效果。E7080明显抑制vegf刺激的微血管内皮细胞的体外增殖。将小细胞肺癌细胞系H1048（产生低量VEGF）和SBC-5（产生中等量VEGF）静脉接种到自然杀伤细胞缺失的严重联合免疫缺陷小鼠体内，导致血液转移到多个器官，包括肝、肺、肾和骨骼，而静脉接种PC14PE6（一种产生大量VEGF的非小细胞肺癌细胞系），导致肺转移伴大量胸腔积液。微转移建立后开始每日应用E7080治疗，可显著减少大转移结节（bbb20 mm）数量和胸腔积液量，延长小鼠生存期。组织学上，E7080治疗降低了转移结节中内皮细胞、淋巴内皮细胞和增殖肿瘤细胞的数量，增加了转移结节中凋亡细胞的数量。这些结果表明E7080具有抗血管生成和抗淋巴管生成活性，可能对非突变型EGFR肺癌和多器官转移患者具有潜在的治疗价值。巨蟹座；10 (7);1218 - 28。(c) 2011年aacr。
While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR-2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell-depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non-small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (>2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases. Mol Cancer Ther; 10(7); 1218-28. (C) 2011 AACR.