1999 Fiscal Year Final Research Report Summary
GENE THERAPY FOR EXPERIMENTAL GLIOMAS USING ADENOVIRUS VECTOR
| Project/Area Number |
10671302
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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 |
ONO Yasuhiro OKAYAMA UNIVERSITY MEDICAL SCHOOL, ASSISTANT, 医学部, 助手 (40294409)
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| Co-Investigator(Kenkyū-buntansha) |
TAMIYA Takashi OKAYAMA UNIVERSITY MEDICAL SCHOOL HOSPITAL, LECTURE, 医学部・附属病院, 講師 (50252953)
MATSUMOTO Kengo OKAYAMA UNIVERSITY MEDICAL SCHOOL, ASSISTANT PROFESSOR, 医学部, 助教授 (10190521)
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| Project Period (FY) |
1998 – 1999
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| Keywords | adenovirus vector / gene therapy / brain tumors / cytosine deaminase / uracil phosphoribosyltransferase / 5-fluorocytosine / 5-fluorouracil |
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| Research Abstract |
One of the transduction methods, denovirus vector, has been shown to transduce exogenous genes successfully into tumor cells both in vitro and in vivo. We have investigated the feasibility of gene transduction for brain tumors using adenovirus vector. On the other hand, suicide gene therapy for brain tumors was the second concern of our research. 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 a suicide gene therapy for various cancers. We also reported the usefulness of 5-FC/CD gene therapy for malignant gliomas in vivo and pointed out its toxicity for normal brain tussues. For the reduction of this toxicity, we combined two genes, that is, CD gene and uracil phosphoribosyltransferase (UPRT) gene, which directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'- monophosphate. 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 brain tumor model, a decreased amount of vectors of CD and UPRT were enough to prolong the survival of rats compared to high dose of CD gene alone and were less toxic for adjacent normal brains. Our data demonstrated that simultaneous CD and UPRT gene expression by adenovirus enhanced the antitumor effect of the 5-FC/CD gene therapy.
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