Establish mentofthe minimally invasive treatments based on biological characteristics for advanceduro logical cancers.

建立基于晚期泌尿系统癌症生物学特性的微创治疗方法。

基本信息

批准号：
07407046
负责人：
TACHIBANA Masaaki
金额：
$ 14.21万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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 … More 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

本研究旨在确定反映泌尿系统癌症侵袭性和恶性潜力的生物学特征，并尝试建立新的治疗方式，作为人类膀胱癌的微创器官保留治疗，可以提供显着的诊断和预后潜力。使用组织学和流式细胞术参数可以提供有关膀胱癌患者临床结果的更多信息我们还研究了作为可能的抑制基因的多个染色体区域的异型性（LOH）的丧失。人类膀胱癌的异常及其与临床结果的关系包含多个抑制基因改变，这些改变表现出更大的遗传不稳定性，因此，对各种易感抑制基因区域的微卫星分析被认为是有用的。确定膀胱癌患者的治疗策略和预后因素已引起人们对联合化疗治疗晚期膀胱癌的关键作用。这种治疗的功效在于确定构成靶肿瘤组织的癌细胞的增殖活性，并能够衡量癌细胞对抗肿瘤药物的反应，令人信服的是，多种药物治疗方案的不同会产生不同的疗效。通过分析化疗药物的细胞动力学特征，确定针对膀胱癌细胞进行联合化疗的最佳时间方案，可以显着增强化疗药物的抗肿瘤效果。与 MTX 和 EP/VBL 联合化疗的同时治疗和/或逆转方案相比，长春花碱 (VBL) 和依托泊苷 (EP) 可以诱导显着的细胞凋亡。调节细胞因子基因表达的转录因子之一，最近被证明是诱导细胞凋亡的调节因子。在本研究中，我们确定产生细胞因子的肿瘤的生长受到 NF-kB 的调节。因此，腺病毒载体对NF-kB的抑制可作为治疗产生细胞因子的膀胱癌相关副肿瘤综合征的有效基因疗法。MAGE是最初从恶性黑色素瘤中克隆的肿瘤排斥抗原。最近在癌症免疫治疗中引起了极大的关注，特别是在诱导肿瘤特异性细胞毒性T细胞（CTL）方面，因为它在各种肿瘤中广泛表达，但在除睾丸和睾丸外的正常细胞中不表达。此外，我们还研究了 NF-kB 是否可以调节 TNF-α 抗性前列腺癌细胞的生长和凋亡，从而阻止 DU-145 和 PC-3 As 细胞中 TNF-α 诱导的细胞死亡。因此，抑制 NF-kB 活化可能是治疗 TNF-α 耐药性前列腺癌细胞的有效疗法。