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

这项研究旨在确定反映泌尿外科癌症的侵入性和恶性潜力的生物特征，并试图建立新的治疗方法作为微创器官保存治疗。用于人类膀胱癌的流式细胞术DNA倍性分析可能会提供明显的诊断和预后潜力。组织学和流式细胞仪参数的联合使用可能会提供有关膀胱癌患者临床结果的其他信息。我们还研究了多个染色体区域的异性症（LOH）的丧失，可能是人类膀胱癌及其与临床结果的关系船对人类膀胱癌的抑制基因异常。高级和攻击性肿瘤包含多种抑制基因改变，表现出更大的遗传不稳定。因此，对各种易感抑制基因区域的微卫星分析被认为可用于确定治疗策略……对于膀胱癌患者，更多的GIE和预后因素。人们非常关注化学疗法以治疗晚期膀胱癌。但是，这种化学疗法的有效性仍然远小于满意度因素。增强这种治疗有效性的关键在于确定构成靶肿瘤组织的癌细胞的增殖活性，并能够评估对癌细胞抗肿瘤剂的反应。令人信服的是，根据其计划，多药治疗的变化有所不同。在本研究中，强调使用化学治疗剂的细胞动力学特征分析针对膀胱癌细胞的最佳组合化疗时间表。与简单治疗和/或与Bladeder癌细胞联合化学疗法中的相比，甲氨蝶呤（MTX）预处理可以显着增强Vinblastine（VBL）和Epopocide（EP）的抗肿瘤作用。核因子KAPPA B（NF-KB）是调节细胞因子基因表达的转录因子之一，最近被证明是诱导凋亡的调节因素。在本研究中，我们确定肌因子产生肿瘤的生长受NF-KB的调节，因此腺病毒载体抑制NF-KB可以用作治疗细胞因子产生Bladeder癌相关副倾向综合综合症的有效基因疗法。黑色素瘤抗原（MAGE）被称为最初来自恶性黑色素瘤的肿瘤排斥抗原。 MAGE最近在癌症免疫疗法中引起了极大的关注，尤其是关于肿瘤特异性细胞毒性T细胞（CTL）的诱导，因为它在各种肿瘤中广泛表达，但在正常细胞中却没有表达，除非睾丸和placeta.Additiondition.Addition。我们在tnf-kb上是否可以调节睾丸和细胞增多症。 NFKB激活可防止DU-145和PC-3细胞中TNFα诱导的细胞死亡。结果，NF-KB激活的抑制可能是对TNF-α-抗α-前列腺癌细胞的有效疗法。