Study on the Molecular Mechanism of Astrocytoma Progression.

本项目旨在分析与P53基因突变相关的星形细胞瘤细胞的恶性表型。本研究取得了以下成果：1)通过p53基因的改变来改变胶质母细胞瘤细胞对化疗药物的敏感性。在34ﾟC时，突变体197L对依托泊苷和紫杉醇的敏感性降低，与37ﾟC相比，突变体197L表现为野生型P53。流式细胞仪分析显示，细胞聚集在Gi期，从而减少了G2M相关的凋亡，这是依托泊苷和紫杉醇的作用所必需的。而对ACNU或顺铂的敏感性不随温度改变而改变。2)在多种胶质母细胞瘤细胞系中，研究了腺病毒载体介导的p53基因转移对细胞生长的抑制作用，其反应依赖于腺病毒-柯萨奇病毒受体(CAR)的表达。野生型p53下调CAR的表达(手稿正在准备中)。3)通过分析胶质母细胞瘤患者的p53基因和其他临床病理参数，证实了p53突变是胶质母细胞瘤更好的放射反应的标志，这导致显著的更长的生存期(癌症资源1998)。

This project has aimed to analyze malignant phenotypes of astrocytoma cells rendered in association with p53 gene mutation. The project has achieved a number of results as follows.1) Modification in sensitivity of glioblastoma cells to chemotherapeutic drugs by p53 alteration was investigated with a glioblastoma cell line harbouring a temperature sensitive p53 mutant 197L.Sensitivity to etoposide and paclitaxel was reduced at 34ﾟC at which the mutant 197L behaves as wild-type p53 as compared to 37ﾟC.In association with this phenomenon, normalization of p53 turnover and activation of p21 and TGF-alpha genes were observed. Flow cytometric analysis demonstrated that the cells accumulated in the Gi phase, and hence reducing G2M associated apoptosis that is essential for effect of etoposide and paclitaxel. In contrast, sensitivity to ACNU or cisplatin was not changed with the temperature modification. (Neuroimmunol Res 1997, and another manuscript in preparation)2) Inhibition of cellular growth by adenoviral vector-media ted p53 gene transfer was investigated in a number of glioblastoma cell lines, Response to the p53 gene transfer was dependent to the expression of Adenovirus-Coxackievirus receptor (CAR). Wild-type p53 down-regulated the CAR expression (manuscript in preparation).3) By analyzing p53 gene and other clinicopathological parameters in glioblastoma patients, it was demonstrated that p53 mutation is a marker of a marker for better radiation response in glioblastomas and this results in significantly longer survival (Cancer Res 1998)