非铂金属配合物增敏替莫唑胺对胶质瘤干细胞的作用及其机制研究

Glioma is the most common and lethal malignancy in central nervous system, and has no effective treatment. Temozolomide (TMZ) is the first-line chemotherapy of glioma drug-naïve, effective but easy to relapse. The resistance mechanism of TMZ is that DNA methyltransferase (MGMT) repair cell damage caused by TMZ. The relative expression levels of MGMT in glioma stem cells (BGSC) are significantly higher than that in glioma cells, avoiding TMZ destruction leading to relapse. Therefore, the search can kill BGSC replacement drugs is the key to improve the cure rate of glioma. In previous work, we found that non-platinum metal complexes can significantly inhibit glioma survive and down MGMT expression, suggesting that it can effectively kill BGSC, therefore this study intends to use the surgical specimens to establish glioma stem cell bank, observe the inhibiting effect of non-platinum metal complex on growth, invasion and tumorigenesis of BGSC ability. Further, we want to establish TMZ resistant BGSC, expression profiling analysis differentially non-platinum complexes on sensitizing effect of TMZ. Finally, gene chip technology to analyze the role of BGSC, reveal the molecular mechanisms associated inhibitory provide a theoretical basis for clinical treatment and drug development.

脑胶质瘤是中枢神经系统中最常见最致命的恶性肿瘤，目前尚无有效治疗手段。替莫唑胺（TMZ）作为胶质瘤的一线化疗药，初治有效但易复发，其耐药机制为DNA甲基转移酶（MGMT）修复TMZ导致的细胞损害。而脑胶质瘤干细胞（BGSC）中MGMT相对表达量明显高于胶质瘤细胞，使BGSC避免被TMZ杀伤，最后导致复发。因此，寻找能有效杀伤BGSC的替代型药物是提高胶质瘤治疗效果的关键。前期工作中，我们发现非铂金属配合物可显著抑制胶质瘤细胞的存活，并下调MGMT的表达，提示其可有效杀伤BGSC,因此本课题拟利用术后标本建立胶质瘤干细胞库，观察非铂金属配合物对BGSC生长、侵袭能力及成瘤性的影响，进一步建立TMZ耐药的BGSC，分析非铂金属配合物对TMZ的增敏作用，最后利用基因芯片技术，分析其作用后BGSC的表达谱差异，揭示其相关的抑瘤分子机制，为临床治疗及新药开发提供理论依据。