2001 Fiscal Year Final Research Report Summary
Development of new tumor specific gene therapy in gastrointestinal carcinoma
| Project/Area Number |
11671180
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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 |
General surgery
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| Research Institution | WAKAYAMA MEDICAL UNIVERSITY, School of Medicine |
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Principal Investigator |
IWAHASHI Makoto Wakayama Medical University, School of Medicine, Associnte Professor, 医学部, 講師 (70244738)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAUE Hiroki Wakayama Medical University, School of Medicine, Professor, 医学部, 教授 (20191190)
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| Project Period (FY) |
1999 – 2001
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| Keywords | gene therapy / Cre / loxP system / CEA promoter / adenovirus vector / orthotopic model / CD / 5-FC suicide gene therapy |
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| Research Abstract |
Tumor-specific gene delivery is crucial to achieving successful effects in suicide gene therapy. Carcinoembryonic antigen (CEA) promoter has been widely used for this purpose, but the expression level of tumor-specific promoters such as CEA promoter is generally low. In this study, we employed the Cre/loxP system, and showed that LacZ expression by CEA promoter was remarkably enhanced while maintaining its specificity using Cre/loxP regulation system. And, the Cre/loxP system was first applied to augmentation of selective expression of cytosine deaminase (CD) gene as a suicide gene therapy in CEA-producing cells. The double infection with AxCEANCre expressing Cre recombinase under control of CEA promoter and AxCALNLCD expressing CD gene under control of CAG promoter by the Cre-switching ststem rendered CEA-producing tumor cells 13-fold more sensitive to 5-FC (5-fluorocytosine) compared with the single infection with AxCEACD expressing CD gene driven by CEA promoter. The therapeutic eff
… More
icacy of the enhanced CD/5-F Csuicide gene therapy was evaluated in orthotopic models of human gastric carcinoma. Adenovirus vectors (1 × 10^9 pfu) were administered i. p. into mice three times, and then 5-FC was administered i. p. for the next 10 days. Tumor volume and weight in mice treated with AxCEANCre and AxCALNLCD were significantly reduced as compared with those in mice treated not only with Mock but also with AxCEACD (p < 0.0001). The survival periods of the mice treated with AxCEANCre and AxCALNLCD /5-FC were longer than those in mice treated with Mock or AxCEACD/5-FC (p < 0.01). Moreover, in orthotopic models of human colon carcinoma, the double administration of AxCEANCre and AxCALNLCD completely inhibited liver metastases, and significantly reduced primary tumor volume compared to the administration of Mock or AxCEACD. These results suggested that the application of Cre/loxP system could provide a new approach for enhanced selective suicide gene therapy of CD/5-FC for the treatment of human gastrointestinal carcinoma. Less
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