Study on the Molecular Mechanism of Astrocytoma Progression.

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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)