| Project/Area Number |
17510058
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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 |
Risk sciences of radiation/Chemicals
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| Research Institution | National Institute of Radiological Sciences |
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Principal Investigator |
NENOI Mitsuru National Institute of Radiological Sciences, Research Center for Radiation Protection, Group Leader (10164659)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUSHITA Satoru National Institute of Radiological Sciences, Fundamental Technology Center, Dupty Director (40165808)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,840,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥240,000)
Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | gene therapy / adeno-associated virus vector / p21 gene / low dose radiation / HSV-tk gene / p21^<WAF1> / HSV-tk |
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| Research Abstract |
In cancer gene therapy, restriction of antitumor transgene expression in a radiation field by use of ionizing radiation-inducible promoters is one of the promising approaches for tumor-specific gene delivery. Although tumor suppressor protein p53 is induced by low doses (<1 Gy) of radiation, there have been only a few reports indicating potential utilization of a p53-target gene promoter, such as that of the p21 gene. This is mainly because the transiently transfected promoter of p53-target genes is not much sensitive to radiation. We examined the response of the p21 gene promoter to low-dose radiation when transduced into a human breast cancer cell line MCF-7 by use of recombinant adeno-associated virus(rAAV)vectors. It was shown that the p21 gene promoter transduced by rAAV vectors was more highly radiation-responsive than that transiently transfected by electroporation. A significant induction of the p21 gene promoter by radiation of low doses down to 0.2 Gy was observed. When cells
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were transduced with the p21 gene promoter-driven HSVtk gene by rAAV vector, they were siginificantly sensitized to repetitive treatment with low dose radiation (1 Gy) in the presence of the prodrug ganciclovir. In addition, we established xenografts by inoculating MCF-7 cells stably transfected with the p21 gene promoter-driven HSVtk gene into the inguinal area of nude mice, and observed a higher sensitivity to repetitive treatment with low dose radiation in the presence of ganciclovir. It was therefore revealed that the p21 gene promoter in combination with a rAAV vector is usable for the development of a low-dose radiation-inducible vector for cancer gene therapy. Next, we investigated the molecular mechanisms for radiation response of the p21 gene promoter for the purpose of development of further highly radiosensitive vectors. And we revealed that a transcription factor Oct-1 was crucial to the regulation of the p21 gene promoter following exposure to clinically relevant doses of radiation. Less
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