Anti-angiogenesis gene therapy utilizing viral vectors

利用病毒载体的抗血管生成基因治疗

基本信息

批准号：
10671325
负责人：
TANAKA Toshihide
金额：
$ 1.15万
依托单位：
Jikei University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671325/
关键词：
Angiogenesis Gene Therapy Viral Vectors Tumor Dormancy angiostatin endostatin endothelial cells apoptosis ascites tumor glioma endostain

项目摘要

The aim of this study is to verify whether viral vector mediated transduction of angiogenesis inhibitor genes containing signal peptide is effective for therapeutics of brain tumor and ascites tumor models.VEGF (vascular endothelial growth factor) plays a major role as stimulator as well as vascular permeability, which result in peritumoral edema, ascites and pleural effusion. First of all, the transduction efficiency to tumor cells and endothelial cells by adenoviral vector expressing β galactosidase was examined. Endothelial cells as well as tumor cells tunied out to be attractive target for gene transduction. Then adenoviral vectors encoding angiogenesis inhibitor such as platelet factor 4 (PF4), angiostatin and endostatin fused to signal peptide was assessed. Vectors mediated therapy against brain and ascites tumor models led to prolonged survival and inhibition of angiogenesis and tumor growth. Secretable form of PF4 (sPF4) was the most effective inhibitor of tumor growth among the all of the angiogenesis inhibitors.In addition, interestingly, gene therapy by sPF4 not only inhibited ascites formation, but also turned bloody tumor associated ascites into yellow and serous fluid. Immunohi stochemical analyzes showed the decreased microvascular density and induction of apoptosis by transduction of angiogenesis inhibitor genes, however, they did not have any effects on growth potency of tumor cells.These results suggest that viral vector mediated anti angiogenesis gene therapy achieved to maintain tumor dormancy. These studies were published in Nature Medicine, Cancer Research, Neurologia Medico-Chirurgica, and Human Gene Therapy.In the future, we will continue to develop further system utilizing other angiogenesis inhibitors such as soluble form of VEGF and Tie-2 receptor to examine whether they have more potent inhibitory effect on tumor growth.

这项研究的目的是验证病毒载体介导的含有信号肽的血管生成抑制剂基因的转导能够有效地治疗脑肿瘤和腹水肿瘤模型。DEVGF（血管内皮生长因子）起着刺激剂以及血管渗透性的主要作用，导致血管渗透性，导致腹膜侵蚀性和plemoral ancustiation和Premoral ancuse ancuse and premal ancuse and premal ancuse and pregusis and fression and preguse and formuse and preguscion and per formuse and preguse and presfemion。首先，检查了表达β半乳糖苷酶的腺病毒载体对肿瘤细胞和内皮细胞的翻译效率。内皮细胞以及肿瘤细胞被调整为具有吸引力的基因转移靶标。然后，评估了编码血管生成抑制剂的腺病毒载体，例如血小板因子4（PF4），Angiostatin和内抑素融合以信号肽。载体介导的针对脑和腹水肿瘤模型的疗法导致长期生存和抑制血管生成和肿瘤生长。 PF4（SPF4）的分泌形式是所有血管生成抑制剂中肿瘤生长最有效的抑制剂。此外，很有趣的是，SPF4的基因治疗不仅抑制了腹水的形成，而且还将血液肿瘤相关的腹水变成黄色和浆液。 Immunohi的高度分析表明，通过转导血管生成抑制剂基因的微血管密度降低和凋亡诱导，但是它们对肿瘤细胞的生长效力没有任何影响。这些结果表明，病毒载体介导的抗血管生成基因治疗可维持肿瘤休眠。这些研究发表在自然医学，癌症研究，神经科医学治疗和人类基因疗法中。未来，我们将继续利用其他血管生成抑制剂（例如固体形式的VEGF和TIE-2受体）开发进一步的系统，以检查它们是否对肿瘤生长具有更大的潜在抑制作用。