| Project/Area Number |
11470347
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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 |
Obstetrics and gynecology
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| Research Institution | SHINSHU UNIVERSITY |
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Principal Investigator |
KONISHI Ikuo Shinshu University, Obstetrics and Gynecology, Professor, 医学部, 教授 (90192062)
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| Co-Investigator(Kenkyū-buntansha) |
MANDAI Masaki Kyoto University, Gynecology and Obstetrics, Assistant Professor, 医学研究科, 助手 (80283597)
TOKI Toshihiko Shinshu University, Obstetrics and Gynecology, Associate Professor, 医学部, 助教授 (20175475)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1999: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Keywords | ovarian cancer / apoptosis / gene therapy / adenovirus / gonadotropin / insulin-like growth factor-1 / p53 / Bax |
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| Research Abstract |
Among the gynecological malignant tumors, ovarian carcinoma is most frequently associated with chemoresistance and poor prognosis of the patients. The effect of chemotherapy with various anti-cancer agents including cisplatin is shown to be mediated by intracellular apoptotic signals. Anti-apoptotic factors, either extrinsic or intrinsic, may influence the chemotherapeutic effect, and may result in the chemoresistance of ovarian cancer cells. Therefore, the objective of our study is to analyze the anti-apoptotic signals in ovarian carcinoma cells, and to develop novel gene therapy targeting these anti-apoptotic signals.
Our study demonstrated that an approximately half of ovarian carcinomas expressed LH/hCG receptor at both mRNA and protein levels. In ovarian cancer cell line OVCAR3 expressing LH/hCG receptors, hCG inhibited cisplatin-induced apoptosis via up-regulation of IGF-1. IGF-1 also inhibited cisplatin-induced apoptosis and a neutralizing antibody to IGF-1 receptor restored the
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apoptosis. Wortmannin, an inhibitor of phosphatidyl inositol 3-kinase, blocked the anti-apoptotic effect of IGF-1. Therefore, gonadotropin is an important extrinsic factor of anti-apoptotic signal in ovarian cancer cell. Treatment with recombinant adenovirus expressing anti-sense IGF-1 mRNA was effective for restoring the cisplatin-induced apoptosis.
Abnormality of p53 tumor suppressor gene is present in more than half of ovarian carcinomas. Pro-apoptotic bax gene is under the regulation of p53, and p53 abnormality resulted in chemoresistance as an intrinsic anti-apototic factor. In vitro, Bax protein expression was attenuated in cisplatin-resistant cell lines such as A2780/cDDP (p53 mutated) and SKOV3 (p53 deleted), compared with cisplatin-sensitive A2780 (p53 wild type). We developed recombinant adenovirus which highly expresses the Bax protein. The Bax protein was successfully induced by treatment with the Bax/adenovirus transfer, and apoptotic effect was obtained in the cisplatin-resistant ovarian cancer cells. Therefore, adenovirus-mediated introduction of Bax may be a useful gene thrapy in the treatment of chemoresistant ovarian carcinomas. Less
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