2002 Fiscal Year Final Research Report Summary
Development of gene therapy for advanced gastrointestinal cancer utilizing novel mutant p53 gene with effective nuclear translocation
| Project/Area Number |
13670535
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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 | Sapporo Medical University |
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Principal Investigator |
TAKAHASHI Minoru 4^<th> Department of Internal Medicine Sapporo Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (60291556)
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| Co-Investigator(Kenkyū-buntansha) |
HAMADA Hirofumi Department of Molecular Medicine Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (00189614)
TERUI Takeshi 4^<th> Department of Internal Medicine Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (50281233)
KATO Junji 4^<th> Department of Internal Medicine Sapporo Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (20244345)
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| Project Period (FY) |
2001 – 2002
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| Keywords | novel mutant p53 / advanced gastrointestinal cancer / gene therapy / adenoviral vector |
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| Research Abstract |
To investigate the feasibility of novel mutant p53 gene (p53/S376A), which mimics the dephosphorylated state p53 by substituting Ser376 with Ala, we constructed adenoviral vectors (AdV) expressing novel mutant p53, or wild type p53 (wtp53) under control of cytomegalovirus immediate early promoter/enhancer (CMVp), respectively resulting in AdCMVp/p53/S376A, AdCMV/wtp53. First we investigated the translocation of p53 after transduction into Hep3B cells, of which p53 status is null/null, infected by AdCMVp/p53/S376A or AdCMV/wtp53. Immunochemiluminescent and western blotting analysis showed that p53/S376A was translocated into nuclear 6 hours after infection clearly earlier translocation to nuclear than that of wild type p53. Next, the effect of the tumor growth suppression by mutant p53 was examined in vitro. The adenovirally-transfered mutant p53 could significantly suppress the tumor growth in comparison with that of wt p53. Extended these results, we then explored the antitumor effect of mutant p53 on subcutaneous xenograft mice model. Intratumoral administration of the AdV expressing mutant p53 showed significant tumor regression and prolongation of survival compared with that of wtp53. Thus, utilization of this novel mutant p53 gene may augment the antitumor effect of p53 gene therapy for cancer and enable tumor-specific promoter to be applicable overcoming the low promoter activity.
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Research Products
(8 results)
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[Publications] Takahashi M, Sato T, Sagawa T, Lu Y, Sato Y, Iyama S, Yamada Y, Fukaura J, Takahashi S, Miyanishi K, Yamashita T, Sasaki K, Kogawa K, Kato J, Niitsu Y: "E1B-55K deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor"Mol.Ther.. 5. 627-634 (2002)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Hagiwara S, Nakamura K, Hamada H, Sasaki K, Ito Y, Kuribayashi K, Sato T, Sato Y, Takahashi M, Kogawa K, Kato J, Terui T, Takayama T, Matsunaga T, Taira K, Niitsu Y: "Inhibition of type I procollagen production by tRNAValCTE-HSP47 ribozyme"J Gene Med. (in press). (2003)
Description
「研究成果報告書概要(欧文)」より
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