| Project/Area Number |
07407046
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Keio University |
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Principal Investigator |
TACHIBANA Masaaki Keio Univ.school of Med.Assistant Prof., 医学部, 講師 (70129526)
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| Co-Investigator(Kenkyū-buntansha) |
ASAKURA Hirotaka Keio Univ.school of Med.Instructor, 医学部, 助手 (50175840)
NAKAMURA Kaoru Keio Univ.school of Med.Assistant Prof., 医学部, 講師 (10146673)
BABA Shiro Keio Univ.school of Med.Associate Prof., 医学部, 助教授 (00051889)
MURAI Masaru Keio Univ.school of Med.Prof., 医学部, 教授 (90101956)
宮川 絢子 慶應義塾大学, 医学部, 助手 (40239356)
大家 基嗣 慶應義塾大学, 医学部, 助手 (00213885)
斉藤 史郎 慶應義塾大学, 医学部, 助手 (80170504)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥22,200,000 (Direct Cost: ¥22,200,000)
Fiscal Year 1997: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1996: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1995: ¥13,200,000 (Direct Cost: ¥13,200,000)
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| Keywords | advanced urological cancers / ogan preserving treatment / nuclear factor kappa B / MAGE / apoptosis / tumorspecific immunotherapy / 進行尿路癌 / 膀胱癌 / 増殖活性 / 尿路上皮癌 / メトトレキセート / ビンブラスチン / G-CSF / 殺細胞効果 / 泌尿器科癌 / 増殖因子 / サイトカイン / autocrine growth / TNF / レチノインサン |
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| Research Abstract |
This study was designed to determine the biological characteristics which reflect invasiveness and malignant potential of urological cancers and try to establish new therapeutic modalities as minimally invasive organ preserving treatments. Flow cytometric DNA ploidy analysis for human bladder cancers may provide significant diagnostic and prognostic potential. Combined use of histological and flow cytometric parameters may offer additional information regarding the clinical outcome for bladder cancer patients. We also studied the loss of heterogygosity (LOH) of the multiple chromosome regions as possible suppressor gene abnormalities on human bladder cancers and their relation ships with clinical outcomes. High-grade and aggressive tumors contain multiple suppressor gene alterations that demonstrate a greater genetic instability. Therefore, a microsatellite analysis of a variety of susceptible suppressor gene regions is considered to be useful in determining both the therapeutic strate
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gies and prognostic factors for patients with bladder cancer. Considerable attention has been given to combination chemotherapy for the treatment of advanced bladder cancer. However, the effectiveness of this chemotherapy remains less than satisfactory. The key to enhancing the efficacy of this treatment lies in ascertaining the proliferating activities of cancer cells composing target tumor tissue and in being able to gauge the response to antitumor agents of cancer cells. It is convincing that there are different efficacies following a variation in multidrug treatment depending on its scheduling. In the present study, emphasis was placed on determining the optimal time schedule of combination chemotherapy administered against bladder cancer cells using an analysis of cell kinetic characteristics of the chemotherapeutic agents. Methotrexate (MTX) pretreatment can significantly enhance the antitumor effects of vinblastine (VBL) and etopocide (EP) when compared with simultaneous treatment and/or the reversed schedule in combined chemotherapy with MTX and EP/VBL against bladder cancer cells, with induction of significant apoptosis. Nuclear factor kappa B (NF-kB) is one of the transcription factors which regulate cytokine gene expression and it was very recently shown to be a regulatory factor for the induction of apoptosis. In the present study, we determined that the growth of sytokine producing tumors was regulated by NF-kB and therefore the inhibition of NF-kB by adenovirus vector can be used as an effective gene therapy for the treatment of cytokine producing bladder cancer associated paraneoplastic syndromes. Melanoma antigen (MAGE) is known as a tumor rejection antigen cloned originally from malignant melanoma. MAGE has recently attracted great attention in cancer immunotherapy, especially regarding the induction of tumor specific cytotoxic T-cells (CTL) because it is widely expressed in various tumors but not in normal cells except for the testis and placenta.
Additionally, we investigated whether or not growth and apoptosis can be regulated by NF-kB on TNF-alpha-resistant prostate cancer cells. NFkB activation prevents TNF-alpha-induced cell death in DU-145 and PC-3 cells. As a result, the inhibition of NF-kB activation may thus be an effective therapy for TNF-alpha-resistant prostate cancer cells. Less
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