Basic research for the combination with anti-angiogenic therapy and heavy charged particle therapy against malignant gliomas

抗血管生成治疗与重带电粒子治疗联合治疗恶性胶质瘤的基础研究

基本信息

批准号：
15591522
负责人：
EHARA Kazumasa
金额：
$ 2.37万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

C6 rat glioma cells were transfected with VEGF164. Spheroids cells were implanted orthotopically into 60 rat brains. Expression of VEGF and fetal liver kinase-1 (VEGF receptor 2) was assessed immunohistochemically. Animals with gliomas received orally administered VEGF inhibitor PTK787/ZK222584. Growth and vascularization were evaluated by magnetic resonance imaging and immunohistochemistry. Early and delayed application of PTK787/ZK222584 in glioma-bearing animals resulted in a reduction of tumor size (71% and 36%) as measured by magnetic resonance imaging volumetry. Vessel density was significantly reduced (42.3% and 25.7%), and areas of intratumoral necrosis were enlarged (by 1.7-fold after early treatment).Additionally, proliferation was decreased by 89% and 72%. There was no growth-inhibiting effect of PTK787/ZK222584 on cells observed. PTK787/ZK222584 significantly halted VEGF-mediated glioma growth by inhibition of neovascularization and proliferation, providing a promising new … More tool in malignant glioma therapy.Rapamycin is a highly specific inhibitor of the mammalian target of rapamycin (mTOR) and has been reported to induce cell cycle arrest and to inhibit VEGF signaling in a broad range of human tumor cell lines. Here, we investigated the effect of rapamycin on cell and tumor growth and in combination with nitrosourea (ACNU, nimustine hydrochloride) in human glioma cells. In established human malignant glioma cells, we confirmed that rapamycin enhanced the apoptosis-inducing effects of ACNU, although treatment with rapamycin alone could not induce apoptosis. Our studies showed that rapamycin inhibited the expressions of p21 protein and mRNA after ACNU treatment in U251MG cells. Moreover, combined treatment of rapamycin and ACNU demonstrated more increase in the Bax/Bcl-xL ratio than ACNU treatment alone. Next, treatment of established intracerebral U251MG xenografts with the rapamycin in vivo resulted in statistically prolonged median survival (p<0.05) compared with control rats. Finally, treatment of established intracerebral U251MG xenografts with the combination of rapamycin and ACNU in vivo resulted in statistically prolonged median survival (p<0.05). These results suggested that combination therapy with mTOR inhibitors and ACNU might be a useful strategy for human malignant gliomas. Less

用VEGF164转化C6大鼠神经胶质瘤细胞。球体细胞原位植入60大鼠大脑。通过免疫组织化学评估VEGF和胎儿肝激酶-1（VEGF接收器2）的表达。具有神经胶质瘤的动物接受口服的VEGF抑制剂PTK787/ZK222584。通过磁共振成像和免疫组织化学评估生长和血管化。通过磁共振成像量测量，早期和延迟应用PTK787/ZK222584在含有神经胶质瘤的动物中的肿瘤大小（71％和36％）的降低。血管密度显着降低（42.3％和25.7％），肿瘤内坏死区域增加（早期治疗后增加1.7倍）。另外，增殖降低了89％和72％。 PTK787/ZK222584对观察到的细胞没有抑制生长的影响。 PTK787/ZK222584通过抑制新血管形成和增殖，显着停止了VEGF介导的胶质瘤的生长，提供了一种有希望的新的……松果素治疗的新工具。黑斑霉素是高度特异性的抑制剂，据报道，乳腺癌含量（MTOR）的含量高度特异人类肿瘤细胞系的。在这里，我们研究了雷帕霉素对细胞和肿瘤生长的影响，并与硝酸（ACNU，盐酸Nimustine）在人神经胶质瘤细胞中的作用。在已建立的人类恶性神经胶质瘤细胞中，我们证实了雷帕霉素增强了ACNU凋亡诱导的作用，尽管仅用雷帕霉素治疗不能诱导凋亡。我们的研究表明，雷帕霉素在U251mg细胞中ACNU处理后抑制了p21蛋白和mRNA的表达。此外，与单独的ACNU治疗相比，雷帕霉素和ACNU的联合治疗表现出的BAX/BCL-XL比的增加更多。接下来，用体内雷帕霉素的脑内U251MG Xenographictics的治疗导致统计延长的中位生存期（P <0.05）与对照大鼠相比。最后，与雷帕霉素和ACNU在体内结合的脑内U251MG Xenographtics的处理可导致统计延长的中位生存期（p <0.05）。这些结果表明，与MTOR抑制剂和ACNU的联合疗法可能是人类恶性神经胶质瘤的有用策略。较少的