Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
Neoplasia. 2011 Jun;13(6):537-49. doi: 10.1593/neo.11258.
Here we investigate the effects of the novel transforming growth factor-β receptor I (TGF-βRI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated MGMT promoter), and endothelial cells (HUVECs) were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67) and the microvessel density (CD31 count), the relative pericyte coverage (α-SMA/CD31 ratio) increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-βRI kinase inhibitor to the present clinical standard (radiation plus TMZ) has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status.
在这里，我们研究了新型转化生长因子-β受体 I（TGF-βRI）丝氨酸/苏氨酸激酶抑制剂 LY2109761 与目前的临床标准联合治疗方案（放疗和替莫唑胺[TＭＺ]）联合应用于胶质母细胞瘤时的作用。我们用 LY2109761、TMZ 和辐射联合处理人胶质母细胞瘤 U87（甲基化 MGMT 启动子）、T98（未甲基化 MGMT 启动子）和内皮细胞（HUVEC）。我们发现 LY2109761 降低了 U87 和 T98 细胞的集落形成存活能力，并进一步增强了辐射诱导的抗集落形成能力。此外，LY2109761 在 Matrigel 迁移和管形成测定中具有抗迁移和抗血管生成作用。在体内，在 BALB/c nu/nu 小鼠皮下生长的人异种移植肿瘤中，LY2109761 单独或与分割放疗和 TMZ 联合使用时可延迟肿瘤生长。有趣的是，正如预期的那样，在所有实验中，甲基化 U87 模型比未甲基化 T98 模型对 TMZ 更敏感，而 LY2109761 则相反。此外，就肿瘤血管生成而言，虽然 LY2109761 降低了胶质母细胞瘤的增殖指数（Ki-67）和微血管密度（CD31 计数），但在三重治疗后，相对周细胞覆盖率（α-SMA/CD31 比值）增加，提示 LY2109761 诱导血管正常化效应。这种正常化可能部分归因于 Ang-2/Ang-1 信使 RNA 比值的降低。LY2109761 还通过非侵入性动态对比增强磁共振成像定量降低了肿瘤血液灌注。总之，这些数据表明，将 TGF-βRI 激酶抑制剂添加到目前的临床标准（放疗加 TMZ）中有可能改善人类胶质母细胞瘤的临床结局，特别是在未甲基化 MGMT 启动子状态的患者中。
