2002 Fiscal Year Final Research Report Summary
Cancer-specific therapy utilizing the Cre recombinase/lox P system
| Project/Area Number |
13670600
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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 |
Respiratory organ internal medicine
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| Research Institution | Osaka University |
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Principal Investigator |
OSAKI Tadashi Osaka University, Department of Molecular Medicine, Assistant Professor, 医学系研究科, 助手 (50324778)
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| Co-Investigator(Kenkyū-buntansha) |
YONEDA Tsutomu Osaka University Hospital, Department of Respiratory Medicine, Medical staff, 医学部附属病院, 医員(臨床研究)
TACHIBANA Isao Osaka University, Department of Molecular Medicine, Assistant Professor, 医学系研究科, 助手 (60324761)
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| Project Period (FY) |
2001 – 2002
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| Keywords | gene therapy / cancer-specific therapy / carcinoembryonic antigen / Cre recombinase / double-infection / adenoviral vector / herpes virus thymidine kinase |
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| Research Abstract |
We investigated whether utilization of the Cre recombinase(Cre) / loxP system contributes to enhanced antitumor effects together with minimal adverse reactions in specific gene therapy against disseminated carcinoembryonic antigen (CEA) -producing cancer cells in the peritoneal cavity of mice. We constructed a pair of recombinant adenoviral vectors (Ads), one of which expresses the Cre gene under the control of the CEA promoter (Ad.CEA-Cre), the other expresses the herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.lox-TK), Coinfection of Ad.CEA-Cre and Ad.lox-TK followed by ganciclovir (GCV) administration significantly suppressed the total tumor weight in the peritoneal cavity of the mice to 13% of that of the untreated mice and 22% of that of the mice treated with Ad.CEA-TK/GCV, an Ad that expressed the HSV-TK gene driven by the CEA promoter alone. Moreover, treatment with Ad.CEA-Cre and Ad.lox-TK/GCV completely rejected tumors in four of ten (40%) mice without significant weight loss, although two of ten mice treated with Ad.CAG-TK/GCV, an adenovirus vector that strongly but non-specifically expressed the TK gene, died due to severe side effects including diarrhea, weight loss, and liver dysfunction. These findings suggest that cell type-specific gene therapy using the Cre/loxP system is effective against disseminated cancer cells without significant side effects. Next, we are now investigating what type of lung cancer patients can be applied to this treatment. Briefly, we recovered tumor cells from lung cancer patients with pleural effusion and evaluated expression of CEA using the quantitative PCR. Simultaneously, we tested the sensitivity of tumor cells to GCV after infection by the Cre/ loxP system and the correlation between CEA expression and GCV sensitivity.
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