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Moleculo-biological analysis for mechanism of proliferation and differentiation in glioma cells and its clinical application

胶质瘤细胞增殖分化机制的分子生物学分析及其临床应用

基本信息

批准号：
04454360
负责人：
SHIMIZU Keiji
金额：
$ 3.58万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

We had already made mouse monoclonal antibodies (ONS-M21) for the antigens which were shared in both glioma and medulloblastoma (Br J Cancer 68 : 831-837,1993). Then we succeed in humanization of their antibodies (Mol Immunol, in press) and their single-chained antibodies in cooperation with Chugai Pharmaceutical Co.Ltd.Using these humanized antibodies and their single-chained antibodies, we might develop the correct diagnoses of tumor sites, and will try to apply to immunotherapy of malignant glioma patients. And now it is in the last steps to extract the malignant glioma-associated antigens which were recognized with these mouse monoclonal antibodies. After extraction of their antigens, we will identify their gene arrangement and mechanisms of their expression. On the other hand, we are researching about the gene therapy for malignant gliomas, with prof. Kazuhiro IKenaka who belong to Okazaki National Research Institutes, National Institute for Physiological Sciences. We published two papers about selective expression of foreign genes in glioma cells by glial-specific promoters (Jpn J Cancer Res 83 : 1244-1247,1992 ; J Neurosci Res 38 : 415-423,1994). At present, we repeats the in vivo gene therapy in mouse glioma models under these in vitro data with the mouse myelin basic protein (MBP) gene promoters to direct toxic gene expression (J Neurosci Res 36 : 472-479,1993). We confirmed that all mice recovered with intraperitoneal administration of GCV,if we could transduced HTK genes into approximately 25% of glioma cells implanted into the mouse brain.If we could elucidate the glioma-associated antigens according to our plans, we will analyze the promoters controlling their manifestation and will apply them in gene therapy with tissue-specificity in the future.

我们已经针对神经胶质瘤和髓母细胞瘤中共有的抗原制备了小鼠单克隆抗体(ONS-M21)(Br J Cancer 68：831-837，1993)。然后我们与中外制药有限公司合作，成功将他们的抗体（MolImmunol，出版中）及其单链抗体人源化。利用这些人源化抗体及其单链抗体，我们可能会开发出肿瘤部位的正确诊断，并将尝试应用于恶性胶质瘤患者的免疫治疗。现在，提取这些小鼠单克隆抗体识别的恶性神经胶质瘤相关抗原已进入最后一步。提取它们的抗原后，我们将鉴定它们的基因排列和表达机制。另一方面，我们正在与教授一起研究恶性胶质瘤的基因治疗。 Kazuhiro IKenaka，隶属于冈崎国立研究所、国立生理科学研究所。我们发表了两篇关于通过神经胶质特异性启动子在神经胶质瘤细胞中选择性表达外源基因的论文(Jpn J Cancer Res 83：1244-1247，1992；J Neurosci Res 38：415-423，1994)。目前，我们在这些体外数据下用小鼠髓鞘碱性蛋白(MBP)基因启动子在小鼠神经胶质瘤模型中重复体内基因治疗以指导毒性基因表达(J Neurosci Res 36：472-479，1993)。我们证实，如果我们能够将HTK基因转导到植入小鼠大脑的大约25%的神经胶质瘤细胞中，那么通过腹腔注射GCV，所有小鼠都会康复。如果我们能够按照我们的计划阐明神经胶质瘤相关抗原，我们将分析控制其表现的启动子，并将其应用于未来具有组织特异性的基因治疗。