| Project/Area Number |
13670489
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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 |
Gastroenterology
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| Research Institution | University of Tsukuba |
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Principal Investigator |
ABEI Masato University of Tsukuba, Institute of Clinical Medicine, Assistant Professor, 臨床医学系, 講師 (20261802)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOYAMA Kazunari RIKEN Institute, Bio Resourse Center, Head, バイオリソースセンター・リソース基盤開発部・遺伝子材料開発室, 室長 (80182707)
TODOROKI Takeshi University of Tsukuba, Institute of Clinical Medicine, Associate Professor, 臨床医学系, 助教授 (70114105)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | gallbladder cancer / gene therapy / adenovirus |
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| Research Abstract |
New treatments, such as gene therapy, are necessary for advanced gallbladder cancer (GBC) but little has been studied. Recent studies have introduced E1 mutant adenoviruses (Ads) which show tumor-specific replication and promising clinical results. To enhance the safety of this approach, we newly constructed AxdAdB-3, a double-restricted Ad with a mutant E1A and E1B-55kD deletion. We studied the in vitro and in vivo effects of this Ad on GBC as well as its safety for normal human cells in comparison with wild-type Ad or an E1B-55kD deleted Ad, AxE1AdB. AxdAdB-3 replicated in and caused oncolysis of several GBC cell lines as efficiently as wild-type Ad or AxE1AdB in vitro. By contrast, AxdAdB-3, replicated much less effectively in primary normal cells (e.g., epithelial cells, endothelial cells and hepatocytes) than in GBC cells and had only a mild cytopathic effects, unlike wild-type Ad. Furthermore, cytotoxicity of AxdAdB-3 in normal cells was milder than AxE1AdB. AxdAdB-3 significantly (p<0.01) suppressed the growth of GBC xenografts. AxdAdB-3 also showed therapeutic efficacy for mice with peritoneally disseminated GBC, showing tumor-selective replication and oncolysis that resulted in significantly (p<0.05) prolonged survival. The present study showed that- the El double-restricted Ad effectively and selectively replicates in and causes oncolysis of GBC in vitro and in vivo with reduced negative effects on normal cells, suggesting that this could be a promising gene therapy tool for GBC.
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