| Project/Area Number |
17590692
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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 | Chiba Cancer Center Research Institute |
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Principal Investigator |
KAWAMURA Kiyoko Chiba Cancer Center Res. Inst., Division of Pathology, Senior Researcher, 病理研究部, 主席研究員 (80260248)
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| Co-Investigator(Kenkyū-buntansha) |
TAGAWA Masatoshi Chiba Cancer Center Res. Inst., Division of Pathology, Head, 病理研究部, 部長 (20171572)
YAMAGUCHI Taketo Chiba University, Graduate School of Medicine, Department of Medicine & Clinical Oncology, Assistant Professor, 医学研究院・腫瘍内科学, 講師 (00241969)
SAISHO Hiromitsu Chiba University, Graduate School of Medicine, Department of Medicine & Clinical Oncology, Professor (10092058)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Transcriptional regulation / Adenovirus / CAR / CD46 / Pancreatic cancer / NF-1 / Tumor promoter / E1 / CD45 / ウイルス増殖 / 腫瘍融解性ウイルス / シャトルベクター / E3ファイバー領域 / 細胞受容体 |
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| Research Abstract |
Adenoviruses (Ad) produce cytotoxic activities and potentially can destroy the infected cells. Ad which are used for gene transduction belong to the type 5 and use the coxsackievirus-adenovirus receptor (CAR) for their cellular receptors. Gastrointestinal tumors including pancreatic tumors however often express the CAR at low levels and consequently the transduction efficacy with the type 5 Ad remained low. On the other hand, type 35 Ad, belonging to the subtype B2 Ad, use CD46 as the cellular receptors, which is expressed at greater levels in tumors than in normal tissues. Since the receptor binding regions are localized in the fiber-knob region (E3-E4), replacement of the type 5 region with the type 35 could achieve better transduction efficacy. We thereby constructed a vector system to produce type 5 Ad bearing the type 35 fiber-knob region and found that the fiber-knob-replaced Ad enabled better transduction efficacy than the prototype 5 in most of tumors tested ; however, our further analyses showed that the efficacy was not directly correlated with the CD46 expression level in pancreatic tumors. We also produced a vector system in which the expression of ElA and E1B, immediate early genes with transcriptional activities, was controlled by exogenous promoters that were active in tumors. The fiber-knob-modified viruses whose ElA and ElB were regulated by the exogenous promoters could induce tumor cell-death with better efficacy than those bearing the type 5 fiber-knob region. The fiber modification however did not improve the efficacy in the CAR-high tumors. Further investigations also showed that the cytotoxic effects were not linked with the ElA protein expression levels and that the effects could be influenced by the cellular factor such as NF-1, which determined the Ad replication activity in the target cells.
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