New therapeutic strategies for malignant brain tumors by using genetic and molecular biology

十多年来，我们对启动子表达髓鞘碱性蛋白（MBP）基因的脑特异性基因治疗控制自杀基因（单纯疱疹病毒胸苷激酶；HSV tK）进行了一些基础性研究。针对这些恶性胶质瘤存在mbp基因高表达或低表达的情况，我们利用一些新的逆转录病毒载体转导表达MAGE-D4基因的启动子（Cancer Res 61: 4809- 4814,2001; gene 277: 129-137, 2001）或其他基因寻找新的高滴度胶质瘤特异性基因治疗方法。选择性基因插入逆转录病毒载体也在进行中。多形胶质母细胞瘤（GBM）在大多数恶性脑肿瘤中表达Olig2转录因子水平很高，可能是由Olig2下调的分化级联分散诱导的。因此，我们开始研究一种新的治疗策略，通过olig2下调因子的转导，将未分化的GBM恢复到非常高的分化阶段。单克隆抗体ONS-M21可识别胶质瘤表面的整合素□3抗原（Br J .肿瘤杂志68:831-837,1993;Br J .肿瘤杂志79:333-339,1999）。然后，我们探讨整合素□3表达与脑胶质瘤患者MAGE-D4基因出现的相关性。我们已经发表了关于半胱抑素C、CDC25B和RCAS1在胶质瘤中的表达。此外，我们开始研究利用小鼠胚胎干细胞诱导的小胶质细胞的迁移活性来进行新的免疫细胞治疗。

For more than 10 years, we have made some fundamental studies on brain-specific gene therapy controlled suicide gene (Herpes Simplex Virus thymidine kinase; HSV tK) with promoter expressed Myelin basic protein (MBP) gene. As these malignant gliomas show high or low MBP-expressed gene, we search a new high-titer glioma-specific gene therapy by using some new retroviral vectors transduced promoter expressing MAGE-D4 gene (Cancer Res 61: 4809-4814, 2001; Gene 277: 129-137, 2001), or other genes. And also selectively gene-inserted retroviral vectors are on-going. As most malignant brain tumors, glioblastomas multiforme (GBM) express Olig2 transcription factors in the very high level, they may be induced by distraction of Olig2-down-regulated differentiation cascade. Therefore, we start in investigate a new therapeutic strategy, which we can restore to the very high differentiated stage from the undifferentiated GBM by transduction of Olig2-down-regulated factors.The monoclonal antibody ONS-M21 recognizes an antigen, which is integrin □3, found on the surface of some gliomas (Br J Cancer 68: 831-837, 1993; Br J Cancer 79: 333-339, 1999). Then, we explore the correlation between integrin □3 expression and MAGE-D4 gene appearance in glioma patients. We had already published about Cystatin C, CDC25B and RCAS1 expressions in gliomas. Besides, we begin to investigate new immuno-cytotherapy by using migration activities of microglia induced from mouse embryonic stem cells.