2002 Fiscal Year Final Research Report Summary
Efficacy of Combination Therapy of Ionizing Radiation and Gene Therapy in Prostate Cancer in vitro
| Project/Area Number |
12670871
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | Kobe University Graduate School of Medicine |
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Principal Investigator |
SOEJIMA Toshinori Kobe University, Graduate School of Medicine, assistant professor, 大学院・医学系研究科, 助教授 (20231384)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRAKAWA Toshiro Kobe University, Graduate School of Medicine, associate professor, 大学院・医学系研究科, 助手 (70335446)
GOTOH Akinobu Kobe University, Graduate School of Medicine, associate professor, 医学部, 助教授 (70283885)
SUGIMURA Kazuro Kobe University, Graduate School of Medicine, professor, 大学院・医学系研究科, 教授 (00136384)
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| Project Period (FY) |
2000 – 2002
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| Keywords | radiation therapy / gene therapy / p53 / adenovirus vector / apoptosis / cell cycle / prostate cancer |
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| Research Abstract |
Several studies have demonstrated that the function of the p53 gene is one of the major determinants of intrinsic cellular sensitivity to the cytotoxic effects of ionizing radiation (IR). Moreover, a strategy to combine adenovirus-mediated wild-type p53 gene transfer with DNA-damaging treatments, such as IR and chemotherapeutic agents, has also been studied in glioblastoma, lung, colorectal, ovarian, and head-and-neck cancers, and additional cytotoxicity or tumor-suppressing activity has been consistently observed. In prostate cancer cells, the significant cytotoxicity has been previously reported with the induction of recombinant wild-type p53 adenovirus (Ad5CMV-p53). In this study, the interactions between IR and Ad5CMV-p53 gene therapy in two androgen-independent prostate cancer cell lines (DU145 and PC-3) were evaluated. We demonstrated that this combination therapy resulted in remarkable synergistic effects and also assessed its molecular mechanisms. The cell growth inhibition in
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DU145 (p53-mutated) cells by IR was strongly enhanced by additional Ad5CMV-p53 infection in a viral dose-dependent manner. In DU145 cells, IR alone induced minimal p53 mRNA expression. However, IR combined with Ad5CMV-p53 infection stimulated significant increase in p53 mRNA expression supplemented with Bax and p21 mRNA expressions. In PC-3 (p53-null), IR induced Bax and p21 mRNA expression, while the combination effects were observed in p53, Bax, and p21 mRNA expression. Apoptotic cell deaths were rarely observed after IR alone (DU145: 3%, PC-3: 5%). However, after combination therapy, the proportion of apoptotic cells greatly increased (sevenfold in DU145 cells, and twice in PC-3 cells). G1 cell cycle arrest was observed after Ad5CMV-p53 infection and the combination in both cell lines. In conclusion, Ad5CMV-p53 infection enhances the effect of radiation therapy by efficient induction of apoptosis and cell cycle arrest. This combination therapy could be one of the optimal treatment strategies for radioresistant prostate cancer. Less
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Research Products
(6 results)
