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。

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07407046/
• 关键词: 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

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肿瘤侵袭性和恶性潜能的生物学特征，并试图建立新的微创器官保留治疗模式。流式细胞DNA倍体分析可为膀胱癌的诊断和预后提供重要的潜力。结合使用组织学和流式细胞术参数可以为膀胱癌患者的临床结果提供额外的信息。我们还研究了人类膀胱癌多染色体区域的杂合性缺失（LOH）作为可能的抑制基因异常及其与临床结果的关系。高级别和侵袭性肿瘤包含多种抑制基因改变，表现出更大的遗传不稳定性。因此，对多种易感抑制基因区域的微卫星分析被认为有助于确定膀胱癌患者的治疗策略和预后因素。联合化疗治疗晚期膀胱癌已受到广泛关注。然而，这种化疗的有效性仍然不令人满意。提高这种治疗效果的关键在于确定组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，不同的多药治疗方案会产生不同的疗效。在本研究中，重点是通过分析化疗药物的细胞动力学特征来确定对膀胱癌细胞进行联合化疗的最佳时间安排。甲氨蝶呤（Methotrexate， MTX）与长春花碱（VBL）和依托泊胺（etopocide， EP）联合化疗对膀胱癌细胞的抗肿瘤作用较MTX和EP/VBL同时治疗和/或相反治疗方案显著增强，并诱导明显的细胞凋亡。核因子κ 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NF-kB的调控，因此腺病毒载体抑制NF-kB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。黑色素瘤抗原（Melanoma antigen， MAGE）是一种从恶性黑色素瘤中克隆出来的肿瘤排斥抗原。由于MAGE在多种肿瘤中广泛表达，而在除睾丸和胎盘外的正常细胞中不表达，因此近年来在肿瘤免疫治疗中引起了广泛的关注，特别是在诱导肿瘤特异性细胞毒性t细胞（CTL）方面。此外，我们还研究了NF-kB是否可以调节tnf - α抵抗前列腺癌细胞的生长和凋亡。NFkB激活可阻止tnf - α诱导的DU-145和PC-3细胞死亡。因此，抑制NF-kB活化可能是治疗tnf - α抵抗性前列腺癌细胞的有效方法。少

项目成果

Tachibana M: "Prognostic significance of flow cytometric deoxyribonucleic acid analysis for patients with superficial bladder cancers" Cancer Detec Prev. in press

Tachibana M：“流式细胞仪脱氧核糖核酸分析对浅表性膀胱癌患者的预后意义”Cancer Detec Prev。

Tacnibana M,et al.: "Constitutive production of multiple cytokines and a human chrionic gonadotrophin beta-subunit by a human bladder cancer cell line (KU-19-19) : possible demonstration of totipotential differentation." Br J Cancer. 76(2). 163-174 (1997)

Tacnibana M 等人：“人膀胱癌细胞系 (KU-19-19) 持续产生多种细胞因子和人绒毛膜促性腺激素 β 亚基：可能证明全能分化。”

Jun Nakashima et al.: "The value of serum carboxyterminal propeptide of type 1 procollagen in predicting Bone Metastases in prostate cancer." J.Urol.(in press).

Jun Nakashima 等人：“1 型前胶原血清羧基末端前肽在预测前列腺癌骨转移中的价值。”

Tachibana M: "Role of proliferative activity estimated by bromodeoxyuridine labeling indexin determining predictive factors of recurrence in superficial intermediately malignant bladder tumors." J Urol. 156(10). 63-63 (1996)

Tachibana M：“通过溴脱氧尿苷标记指数估计的增殖活性在确定浅表中度恶性膀胱肿瘤复发的预测因素中的作用。”

橘政昭: "腎臓学 病態生理からのアプローチ" 黒川清, 442 (1995)

Masaaki Tachibana：“肾病学：病理生理学方法” Kiyoshi Kurokawa，442 (1995)