| Project/Area Number |
17591737
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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 |
Obstetrics and gynecology
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| Research Institution | Tottori University |
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Principal Investigator |
ITAMOCHI Hiroaki Tottori University, Hospital, Associate Professor (20314601)
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| Co-Investigator(Kenkyū-buntansha) |
KIGAWA Junzo Tottori University, Hospital, Professor (00177784)
TARAKAWA Naoki Tottori University, 医学部, Professor (90163906)
SHIMADA Muneaki Maori University, Faculty of Medicine, Assistant Professor (40362892)
OISHI Tetsuro Tottori University, Faculty of Medicine, Assistant Professor (80359877)
SATO Shinya Tottori University, Hospital, Assistant Professor (10423261)
金森 康展 鳥取大学, 医学部附属病院, 講師 (70283984)
高橋 正国 鳥取大学, 医学部, 助手 (30379622)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,810,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Carcinoma / Gene therapy / Chemoresponse |
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| Research Abstract |
Resistance of ovarian clear cell carcinoma (CCC) to platinum-based chemotherapy is associated with poor prognosis, and an effective treatment for advanced disease is urgently needed. HER2/neu is up-regulated more often in CCC than in other histologic types of epithelial ovarian cancer. The purpose of this study was to assess possible treatment for ovarian CCC with the anti-HER2 antibody tanstuzumab or human adenovirus type 5 E1A. We treated 10 CCC cell lines with transtuzumab or E1A and assessed cell viability, proliferation, and colony formation and the expression of HER2 and wild-type p53 proteins and molecules downstream of those signaling pathways. HER2 protein was detected at various levels in all 10 cell lines by Western blotting and in 5 CCC cell lines by immunohistochemical staining: HER2 gene amplification was detected (by fluorescence in situ hybridization) in only one cell line (RMG-I). Trastuzumab did not inhibit proliferation in any of the four CCC cell lines tested (RMG-I, SKOV-2, OVTOKO, and OVSAYO). However, transfection with E1A (as compared with control vectors) reduced colony formation in all 10 CCC cell lines regardless of HER2 expression level. Infection of RMG-I and SMOV-2 cells with an adenoviral vector encoding E1A led to significant (P<0.05) suppression of proliferation and enhancement of cell death; this effect required stabilization of p53 (but not p73) protein and was associated with the up-regulation of Bax and the cleavage of caspase9. Other mechanisms, such as p53-independent apoptosis, may also be involved in E1A-mediated cell death in CCC. Finally, treatment with E1A prolonged survival in a CCC xenograft model (P<0.001). E1A gene therapy, because of its ability to stabilize wild-type p53, is worth exploring as a treatment modality for women with ovarian CCC, which typically expresses wild-type p53.
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