E7080, a Multi-Tyrosine Kinase Inhibitor, Suppresses the Progression of Malignant Pleural Mesothelioma with Different Proangiogenic Cytokine Production Profiles
E7080, a Multi-Tyrosine Kinase Inhibitor, Suppresses the Progression of Malignant Pleural Mesothelioma with Different Proangiogenic Cytokine Production Profiles
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DOI：
10.1158/1078-0432.ccr-09-1980
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发表时间：
2009-12-01
影响因子：
11.5
通讯作者：
Sone, Saburo
中科院分区：
文献类型：
--
作者：
Ikuta, Kenji;Yano, Seiji;Sone, Saburo
目的：恶性胸膜间皮瘤（MPM）是一种生物学异质性恶性疾病，预后差。我们以前报道，抗血管内皮生长因子（VEGF）抗体，贝伐单抗，有效地抑制原位移植模型中VEGF高生产（但不是VEGF低生产）MPM细胞的进展，表明需要新的治疗策略，以改善这种疾病的不良预后。因此，我们集中在多酪氨酸激酶抑制剂E7080和评估其对具有不同促血管生成细胞因子产生谱的MPM细胞的治疗功效。实验设计：在原位植入三种人MPM细胞系的严重联合免疫缺陷小鼠模型中测定E7080的功效结果：在促血管生成细胞因子产生方面，MSTO-211 H和Y-MESO-14细胞分别是产生高水平成纤维细胞生长因子-2和VEGF的MPM细胞。NCI-H290细胞产生低水平的成纤维细胞生长因子-2和VEGF相比，其他两个细胞系。E7080有效地抑制VEGF受体-2和FGF受体1的磷酸化，因此，在体外抑制内皮细胞的增殖，但不抑制MPM细胞系的增殖。原位接种的MSTO-211 H细胞仅产生胸部肿瘤，而NCI-H290和Y-MESO-14细胞也产生胸腔积液。治疗E7080有力地抑制了这三个MPM细胞系的进展，并显着延长小鼠的生存，这是与肿瘤相关的血管和增殖的MPM细胞在tumor.Conclusions的数量减少：这些结果强烈表明广谱活性的E7080对MPM与不同的促血管生成细胞因子的生产配置文件在人类。(Clin Cancer Res 2009;15（23）：7229-37）
Purpose: Malignant pleural mesothelioma (MPM) is a biologically heterogeneous malignant disease with a poor prognosis. We reported previously that the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, effectively inhibited the progression of VEGF-high-producing (but not VEGF-low-producing) MPM cells in orthotopic implantation models, indicating the need for novel therapeutic strategies to improve the poor prognosis of this disease. Therefore, we focused on the multityrosine kinase inhibitor E7080 and assessed its therapeutic efficacy against MPM cells with different proangiogenic cytokine production profiles.Experimental Design: The efficacy of E7080 was assayed in orthotopic implantation of severe combined immunodeficient mouse models with three human MPM cell lines (MSTO-211H, NCO-H290, and Y-MESO-14).Results: With regard to proangiogenic cytokine production profiles, MSTO-211H and Y-MESO-14 cells were MPM cells producing high levels of fibroblast growth factor-2 and VEGF, respectively. NCI-H290 cells produced low levels of fibroblast growth factor-2 and VEGF compared with the other two cell lines. E7080 potently suppressed the phosphorylation of VEGF receptor-2 and FGF receptor 1 and, thus, inhibited proliferation of endothelial cells, but not that of the MPM cell lines, in vitro. Orthotopically inoculated MSTO-211H cells produced only thoracic tumors, whereas NCI-H290 and Y-MESO-14 cells also developed pleural effusions. Treatment with E7080 potently inhibited the progression of these three MPM cell lines and markedly prolonged mouse survival, which was associated with decreased numbers of tumor-associated vessels and proliferating MPM cells in the tumor.Conclusions: These results strongly suggest broad-spectrum activity of E7080 against MPM with different proangiogenic cytokine production profiles in humans. (Clin Cancer Res 2009;15(23):7229-37)