Molecular targeted and gene therapy using adeno-associated virus vector to suppress the peritoneal dissemination in ovarian cancer

使用腺相关病毒载体抑制卵巢癌腹膜播散的分子靶向和基因治疗

基本信息

批准号：
17591755
负责人：
OHWADA Michitaka
金额：
$ 2.37万
依托单位：
Jichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

The main mode of progression is a peritoneal dissemination in ovarian cancer, and a peritoneal dissemination is involved of the angiogenesis factors those of vascular endothelial growth factor(VEGF), hepatocyte growth factor (HGF) and so on. We performed to investigate the molecular targeted and gene therapy using adeno-associated virus (AAV) vector for the purpose of the inhibition of peritoneal dissemination in ovarian cancer.We revealed as follows ;(1)AAV vectors are derived from a nonpathogenic virus, and a long-term transgene expression can be obtained after intramuscular vector injection and the serotype-1 was most useful.(2)Soluble Flt-1 (sFlt-1) and interleukin-10 (IL-10) are potentially useful as an antagonist of VEGF. By using AAV-sFlt-land AAV-Il-10, inhibition of peritoneal dissemination and long-term survival were showed in tumor bearing mice by means of anti-angiogenesis. Rare adverse events were found.(3)Ovarian cancer cell line overexpressed HGF/NK4 (HRA/NK4) showed that inhibitions of cell migration in virto and peritoneal dissemination in vivo. It suggested that inhibition of peritoneal dissemination of HGF/NK4 work by cell migration.(4)HGF/NK4 was overexpressed of 22 genes including proline dehydrogenase and porin, and underexpressed of 12 genes including FLIP, EphB1 and tyrosine kinase DDR more than control by microarray analysis. EphB1 and tyrosine kinase DDR were involved cell migration.These results indicated that sFlt-1, IL-10 and AAV-HGF/NK4 suppress tumor growth and peritoneal dissemination of ovarian cancer by inhibition of angiogenasis, and thus suggest the usefulness of gene therapy for ovarian cancer.

进展的主要模式是卵巢癌的腹膜传播，腹膜传播涉及血管生成因子血管生长因子（VEGF），肝细胞生长因子（HGF）等。 We performed to investigate the molecular targeted and gene therapy using adeno-associated virus (AAV) vector for the purpose of the inhibition of peritoneal dissemination in ovarian cancer.We revealed as follows ;(1)AAV vectors are derived from a nonpathogenic virus, and a long-term transgene expression can be obtained after intramuscular vector injection and the serotype-1 was most有用的。（2）可溶性FLT-1（SFLT-1）和白介素-10（IL-10）有可能作为VEGF的拮抗剂。通过使用AAV-SFLT-LAND AAV-IL-10，通过抗血管生成显示了腹膜传播和长期生存的抑制作用。发现罕见的不良事件。（3）卵巢癌细胞系过表达的HGF/NK4（HRA/NK4）表明，体内的Viro和腹膜传播中细胞迁移的抑制作用。它表明，通过细胞迁移对HGF/NK4的腹膜传播的抑制作用。（4）HGF/NK4的22个基因过表达，包括脯氨酸脱氢酶和孔蛋白，以及12个基因，包括FLIP，EPHB1和酪氨酸激酶DDR多于对照组的12个基因。 EPHB1和酪氨酸激酶DDR涉及细胞迁移。这些结果表明SFLT-1，IL-10和AAV-HGF/NK4抑制肿瘤的生长，并通过抑制血管生成纳斯的卵巢癌，从而抑制卵巢癌，从而暗示基因治疗卵巢癌的有用性。