Synergistic antiglioma activity of radiotherapy and enzastaurin
Synergistic antiglioma activity of radiotherapy and enzastaurin
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DOI：
10.1002/ana.21057
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发表时间：
2007-02-01
影响因子：
11.2
通讯作者：
Wick, Wolfgang
中科院分区：
文献类型：
--
作者：
Tabatabai, Ghazaleh;Frank, Brigitte;Wick, Wolfgang
目的：放射治疗是恶性胶质瘤的重要治疗手段，但在实验性胶质瘤中，放射治疗会促进胶质瘤细胞的侵袭，从而产生不良反应。此外，放射诱导血管内皮生长因子（VEGF）的水平在胶质瘤，这是与预后不良。在这里，我们调查的蛋白激酶C-β抑制剂enzaelutin（ENZA）和放射治疗在体外和体内的比较与任一treatments.Methods：我们分析了ENZA和放射治疗对胶质瘤细胞迁移，凋亡和增殖，以及VEGF分泌的影响在体外。在小脑颗粒神经元中评估ENZA的神经毒性。LNT-229胶质瘤细胞裸鼠原位脑内种植后，分析原位脑照射和口服ENZA对裸鼠生存期、肿瘤大小、VEGF表达、细胞凋亡和微血管密度的影响。ENZA可缩小肿瘤体积、辐射诱导的肿瘤卫星形成、在体外和体内上调VEGF表达以及增强体内微血管密度。重要的是，ENZA在体外或在vivo.Interpretation中没有神经毒性：放疗后长期给予ENZA是可行的，并导致无神经毒性的长期生存。
Objective: Radiotherapy is an essential treatment modality for malignant gliomas, but it exerts adverse effects via promotion of glioma cell invasion in experimental glioma. Furthermore, irradiation induces vascular endothelial growth factor (VEGF) levels in gliomas, which is associated with poor prognosis. Here, we investigate the combination of the protein kinase C-beta inhibitor enzastaurin (ENZA) and radiotherapy in vitro and in vivo in comparison with either treatment alone.Methods: We analyzed the effects of ENZA and irradiation on migration, apoptosis, and proliferation of glioma cells, as well as VEGF secretion in vitro. Neurotoxiciuy of ENZA was assessed in cerebellar granule neurons. After orthotopic intracerebral implantation of LNT-229 glioma cells in nude mice, the effects of in situ cerebral irradiation and oral application of ENZA on survival, tumor size, VEGF expression, apoptosis, and microvessel density in vivo were analyzed.Results: Combining cerebral irradiation with ENZA leads to longer survival in vivo. ENZA diminishes tumor volume, irradiation-induced tumor satellite formation, upregulation of VEGF expression in vitro and in vivo, as well as enhanced microvessel density in vivo. Importantly, ENZA is not neurotoxic in vitro or in vivo.Interpretation: Long-term administration of ENZA after radiotherapy is feasible and leads to long-term survival without neurotoxicity.