BACKGROUND The treatment of glioblastomas (GBM) is still a clinical challenge. Current GBM therapeutic plans focus on the development of new strategies for local drug administration in the tumor cavity to realize an efficient long-term treatment with small side-effects. Here, different amounts of residual GBM cells and healthy brain cells define the microenvironment of the tumor cavity after individual surgical GBM resection (complete or incomplete). METHODS We evaluated available in vivo data and determined the required amounts and numerical ratios of GBM and healthy brain cells for our in vitro (in)complete resection dual co-culture model. We applied a generic two-drug treatment [Temozolomide (TMZ) in combination with AT101, followed by single AT101 treatment] strategy and analyzed the results in comparison with appropriate mono-culture systems to prove the applicability of our model. RESULTS We established a suitable GBM dual co-culture model, mimicking the complete and incomplete resection in vitro, giving stable and reliable results on drug testing. Both dual co-culture conditions protectively influenced on cell death and growth rates of primary GBMs when treated with TMZ+AT101/AT101, although the treatment strategy per se was still efficient. Cell death of astrocytes correlated with amounts of increasing GBM cell numbers in the incomplete resection model upon drug treatment, and probably GBM-released chemokine and cytokines were involved in this interplay. CONCLUSIONS Our results suggest that this dual co-culture model provides a biologically relevant platform for the discovery and compound screening of local GBM treatment strategies.

中文翻译：

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建立适用于药物测试的胶质母细胞瘤体外（完整）双重共培养模型。

背景技术胶质母细胞瘤（GBM）的治疗仍然是临床挑战。当前的GBM治疗计划专注于在肿瘤腔中局部给药的新策略的开发，以实现具有小副作用的有效的长期治疗。在这里，不同数量的残余GBM细胞和健康的脑细胞定义了单个外科GBM切除术后（完全或不完全）的肿瘤腔的微环境。方法我们评估了可用的体内数据，并确定了我们体外（不完全切除）双重共培养模型所需的GBM和健康脑细胞的数量和数量比。我们将通用的两药疗法[替莫唑胺（TMZ）与AT101，然后采用单AT101处理]策略，并与适当的单培养系统比较分析结果，以证明我们的模型的适用性。结果我们建立了合适的GBM双重共培养模型，模拟了体外完整和不完整的切除，从而在药物测试中提供了稳定可靠的结果。当用TMZ + AT101 / AT101处理时，两种双重共培养条件都对细胞死亡和原发性GBM的生长产生了保护性影响，尽管其治疗策略本身仍然有效。在药物治疗后，不完全切除模型中星形胶质细胞的细胞死亡与增加的GBM细胞数量相关，并且可能是GBM释放的趋化因子和细胞因子参与了这种相互作用。