| Project/Area Number |
14571519
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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 |
Urology
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| Research Institution | Kitasato University |
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Principal Investigator |
INE Akira Kitasato University, Medicine, Assistant Professor, 医学部, 講師 (50193694)
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| Co-Investigator(Kenkyū-buntansha) |
IWAMURA Masatsugu Kitasato University, Medicine, Assistant Professor, 医学部, 講師 (20176564)
SOH Shigehiro Kitasato University, Medicine, Research Associate, 医学部, 助手 (30206669)
SATOH Takefumi Kitasato University, Medicine, Research Associate, 医学部, 助手 (50286332)
志村 哲 北里大学, 医学部, 助手 (40216114)
丸 典夫 北里大学, 医学部, 助手 (00245432)
奥野 紀彦 北里大学, 医学部, 助手 (80317031)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | gene therapy / bladder cancer / adenovirus / CAR / erbB2 / ribozyme / p53 |
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| Research Abstract |
Antitumor efficacy of an adenoviral vector (Ad-p53/erbB2Rz), which simultaneously expresses wild-type p53 and anti-erbB2 ribozyme, was evaluated against human bladder cancer cells. Expression of the targeted genes and their encoded proteins was sufficiently modulated by the adenoviral infection, and cell growth was inhibited dose-dependently. The therapeutic efficacy of this virus was superior to other control viruses those express single therapeutic genes, i.e., p53 or erbB2 ribozyme, when the amount of viral titer was same, even when these viruses were used in combination. Decreasing the amount of viruses resulted in reduced nonspecific vector-related cytotoxicity.
For enhancing the therapeutic efficacy, improvement of adenoviral infectivity to bladder cancer cells was aimed. Cocsackie-Adenovirus Receptor (CAR) plays crucial role in adenoviral infection, and the decreased expression of CAR in high-grade bladder cancer has been reported. CAR expression and adenoviral infectivity were evaluated in several bladder cancer cell lines, and unstable expression profile of CAR and unsteady adenoviral infectivity were observed depending on the condition of cultured cells. These phenomenons were related strongly to passage numbers and density of the cells. Fiber-mutant adenovirus (Ad5/F35) was then employed for overcoming this unstable adenoviral infectivity to bladder cancer cells. CAR expression is not required in infection of Ad5/F35, and CD46 was revealed as the receptor of this virus. The expression CD46 was evaluated in several bladder cancer cell lines, and stable strong expression was demonstrated in most cell lines unlike CAR expression. The infectivity of Ad5/F35 was superior to Ad5 in most bladder cancer cells, especially in high-grade tumors. This fiber-mutant adenoviral vector might have strong impact on bladder cancer gene therapy.
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