| Project/Area Number |
09671425
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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 |
Cerebral neurosurgery
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
TAMIYA Takashi Okayama University Medical School Hospital, Lecture, 医学部・附属病院, 講師 (50252953)
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| Co-Investigator(Kenkyū-buntansha) |
ONO Yasuhiro Okayama University Medical School, Assistant, 医学部, 助手 (40294409)
MATSUMOTO Kengo Okayama University Medical School, Assistant Professor, 医学部, 助教授 (10190521)
古田 知久 岡山大学, 医学部・附属病院, 助教授 (30181457)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | adenovirus vector / gene therapy / brain tumors / cytosine deaminase / 5-fluorocytosine / 5-fluoruoracil / chemosensitivity gene / uracil phosphoribosyltransferase / adenovirus vector / brain tumors / gene therapy / chemosensitivity gene / retrovirus vector / E.coli gpt gene / 6-thioxanthine |
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| Research Abstract |
Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluoruoracil (5-FU) to 5-fluoruorridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that UPRT-transduced 9L cells mediated by an adenovirus were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared to that of CD alone. In a rat brain tumor model, a decreased amount of vectors of CD and UPRT were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD+UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.
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