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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转染C6大鼠胶质瘤细胞。将球形细胞原位植入60只大鼠脑内。免疫组织化学检测VEGF和胎肝激酶-1 （VEGF受体2）的表达。胶质瘤动物口服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形成。磁共振成像体积测量显示，PTK787/ZK222584在胶质瘤动物中的早期和延迟应用导致肿瘤大小减小（71%和36%）。血管密度明显降低（42.3%和25.7%），瘤内坏死面积增大（早期治疗后增大1.7倍）。细胞增殖能力分别下降89%和72%。PTK787/ZK222584对细胞无生长抑制作用。PTK787/ZK222584通过抑制新生血管和增殖，显著阻止vegf介导的胶质瘤生长，为恶性胶质瘤治疗提供了一个有希望的新工具。雷帕霉素是哺乳动物雷帕霉素靶蛋白（mTOR）的高度特异性抑制剂，据报道，在多种人类肿瘤细胞系中，雷帕霉素可诱导细胞周期阻滞并抑制VEGF信号传导。在这里，我们研究了雷帕霉素对人胶质瘤细胞和肿瘤生长的影响，以及与亚硝基脲（ACNU，盐酸尼莫司汀）联合使用。在已建立的人恶性胶质瘤细胞中，我们证实了雷帕霉素增强ACNU诱导凋亡的作用，尽管雷帕霉素单独治疗不能诱导细胞凋亡。我们的研究表明，雷帕霉素抑制ACNU处理后U251MG细胞p21蛋白和mRNA的表达。此外，雷帕霉素联合ACNU治疗的Bax/Bcl-xL比单独ACNU治疗的Bax/Bcl-xL增加更多。接下来，体内用雷帕霉素治疗已建立的脑内U251MG异种移植物，与对照组相比，中位生存期有统计学延长（p<0.05）。最后，体内联合雷帕霉素和ACNU治疗已建立的脑内U251MG异种移植物，统计学上延长了中位生存期（p<0.05）。这些结果提示mTOR抑制剂和ACNU联合治疗可能是治疗人类恶性胶质瘤的有效策略。少