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.

本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基因的转导对于脑肿瘤和腹水肿瘤模型的治疗是否有效。VEGF（血管内皮生长因子）在刺激剂和血管通透性方面发挥着重要作用，导致瘤周水肿、腹水和胸腔积液。首先，表达β的腺病毒载体对肿瘤细胞和内皮细胞的转导效率。检查了内皮细胞以及肿瘤细胞，这些细胞被认为是基因转导的有吸引力的靶点，然后评估了编码血管生成抑制剂（例如血小板因子4（PF4）、血管抑制素和内皮抑素）的载体介导的治疗。脑和腹水肿瘤模型可延长存活时间并抑制血管生成和肿瘤生长，分泌型 PF4 (sPF4) 是最有效的肿瘤抑制剂。此外，有趣的是，sPF4基因治疗不仅抑制腹水形成，而且使血性肿瘤相关腹水变成黄色浆液性液体，免疫组织化学巢显示微血管密度降低并诱导细胞凋亡。然而，血管生成抑制基因的转导对肿瘤细胞的生长能力没有任何影响。这些结果表明，病毒载体介导的抗血管生成基因治疗实现了维持肿瘤休眠。发表在《Nature Medicine》、《Cancer Research》、《Neurologia Medico-Chirurgica》和《Human Gene Therapy》上。未来，我们将继续开发利用其他血管生成抑制剂（例如可溶形式的 VEGF 和 Tie-2 受体）的进一步系统，以检查它们是否具有对肿瘤生长有更强的抑制作用。