| Project/Area Number |
10557126
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
SAWAMURA Yutaka Hokkaido Univ., Hosp., Lec., 医学部・附属病院, 講師 (10235476)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRATO Hiroki Hokkaido Univ., Grad.School of Med., Asso.Prof., 大学院・医学研究科, 助教授 (20187537)
TADA Mitsuhiro Hokkaido Univ., Institute for Genetic Med., Asso.Prof., 遺伝子病制御研究所, 助教授 (10241316)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥11,500,000 (Direct Cost: ¥11,500,000)
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| Keywords | p53 tumor suppressor gene / cell cycle regulators / apoptosis / chemosensitivity / sensitivity to radiation / high grade astrocytoma / gene therapy |
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| Research Abstract |
Our study on p53 gene mutation in astrocytic tumors disclosed the importance to understand how low grade tumors recur and progress to malignant lesions since this dramatically shortens patient survival. Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor. Frequent co-alterations of TP53, p16/CDKN2A, p14 (ARF), PTEN tumor suppressor genes indicate the importance of developing therapeutic approaches applicable to tumors with a broad range of genetic alterations. In order to understand the influence of the functional status of p53 on the sensitivity to anticancer agents and radiotherapy, we analyzed responses of LN382 cells containing a temperature-sensitive mutant p53 at 34 degrees and 37 degrees to etoposide, paclitaxel, cisplatin, and ACNU.Restoration of p53 protein function in LN382 cells at 34 degrees reduced the cytotoxicity of etoposide and paclitaxel, whereas that of cisplatin, but not of ACNU.Transduction of wild-type p53 in LN382 cells also reduced the sensitivity of the cells to etoposide. Cell cycle analysis revealed that this decrease in sensitivity was associated with an impaired transition to the G2M phase subsequent to the addition of etoposide or paclitaxel. The cell cycle arrest induced by wild-type p53 function may abrogate the cytotoxic effects of etoposide and paclitaxel, which are dependent on G2M-associated apoptosis. On the other hand, p21 expression by restoration of p53 function can increase the radiosensitivity of glioblastoma cells by arresting the cells at G1 and G2M phases. To study the feasibility of gene therapy in malignant gliomas, we examined the antiproliferative effect of the adenovirally transduced wild-type p53 tumor suppressor gene by using 15 different high-grade glioma cell lines and found that CAR expression is a critical determinant of transduction efficiencies in adenovirus-based gene therapy for human malignant gliomas.
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