Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
Clin Cancer Res. 2009 Dec 1;15(23):7229-37. doi: 10.1158/1078-0432.CCR-09-1980. Epub 2009 Nov 24.
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 multi-tyrosine kinase inhibitor E7080 and assessed its therapeutic efficacy against MPM cells with different proangiogenic cytokine production profiles.
The efficacy of E7080 was assayed in orthotopic implantation of severe combined immunodeficient mouse models with three human MPM cell lines (MSTO-211H, NCI-H290, and Y-MESO-14).
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.
These results strongly suggest broad-spectrum activity of E7080 against MPM with different proangiogenic cytokine production profiles in humans.
恶性胸膜间皮瘤（MPM）是一种生物学异质性恶性疾病，预后不良。我们之前曾报道过，抗血管内皮生长因子（VEGF）抗体贝伐单抗有效抑制了 VEGF 高表达（而非 VEGF 低表达）的 MPM 细胞在原位移植模型中的进展，这表明需要新的治疗策略来改善这种疾病的不良预后。因此，我们专注于多酪氨酸激酶抑制剂 E7080，并评估其对具有不同促血管生成细胞因子产生谱的 MPM 细胞的治疗效果。
在三种人 MPM 细胞系（MSTO-211H、NCI-H290 和 Y-MESO-14）的原位植入严重联合免疫缺陷小鼠模型中检测 E7080 的疗效。
就促血管生成细胞因子产生谱而言，MSTO-211H 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。与其他两种细胞系相比，NCI-H290 细胞产生的成纤维细胞生长因子-2 和 VEGF 水平较低。E7080 能够强烈抑制 VEGF 受体-2 和 FGF 受体 1 的磷酸化，从而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-211H 细胞仅产生胸腔肿瘤，而 NCI-H290 和 Y-MESO-14 细胞也产生胸腔积液。E7080 治疗强烈抑制了这三种 MPM 细胞系的进展，并显著延长了小鼠的存活时间，这与肿瘤中肿瘤相关血管和增殖性 MPM 细胞数量的减少有关。
这些结果强烈表明，E7080 对人类具有不同促血管生成细胞因子产生谱的 MPM 具有广谱活性。
