2004 Fiscal Year Final Research Report Summary
Immunogene therapy for hepatocellular carcinoma : combination with local gene therapy
| Project/Area Number |
14370185
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Kagawa University |
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Principal Investigator |
KURIYAMA Shigeki Kagawa University, Third Department of Internal Medicine, Professor, 医学部, 教授 (50244710)
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| Co-Investigator(Kenkyū-buntansha) |
KUROKOHCHI Kazutaka Kagawa University, Third Department of Internal Medicine, Research Assistant, 医学部, 助手 (10294753)
MASAKI Tsutomu Kagawa University, Third Department of Internal Medicine, Research Assistant, 医学部, 助手 (30335848)
YOSHIJI Hitoshi Nara Medical University, Third Department of Internal Medicine, Research Assistant, 医学部, 助手 (40336855)
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| Project Period (FY) |
2002 – 2004
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| Keywords | gene therapy / hepatocellular carcinoma / adenovirus / retrovirus / immunity / cell cycle / tumor suppressor gene / vascularization |
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| Research Abstract |
To establish clinically applicable gene therapy for hepatocellular carcinoma (HCC), we carried out several basic researches. Firstly, to examine molecules that play important roles in hepatocarcinogenesis, we assessed the expression of cell cycle-related molecules during the natural HCC development in Long-Evans Cinnamon rats, an animal HCC model. It was shown that the expression of cyclin-dependent kinase 4 (Cdk4) and p46 Shc was increased significantly during hepatocarcinogenesis, while that of cyclin D1 and Cdk6 was not. Furthermore, analyses of human HCC and the adjacent non-HCC cirrhotic liver samples revealed that the expression of p18^<INK4c> was decreased significantly in human HCC compared with the adjacent cirrhotic tissues. It was also shown that the prognosis of patients with HCC negative for p18^<INK4c> was significantly poorer compared with those with HCC positive for p18^<INK4c>. Secondly, we demonstrated that the inhibition of vascular endothelial growth factor receptors in HCC resulted in attenuation of HCC development in rodents. Thirdly, we demonstrated that repetitive intrabiliary administration of adenoviral vectors could induce repetitive transgene expression in rat livers without any immunosuppressive strategies. These results support the feasibility of gene therapy for HCC, because candidates of target molecules for genetic manipulation and delivery routes of recombinant adenovirus were suggested.
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