Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo
Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo
复制标题
DOI：
10.1038/sj.gt.3301912
复制
发表时间：
2003-03-01
期刊：
影响因子：
5.1
通讯作者：
Miki, T
中科院分区：
文献类型：
--
作者：
Nakanishi, H;Mazda, O;Miki, T
为了实现针对前列腺癌（PC）的有效的非病毒基因治疗，使用含有EBNA 1基因和oriP的基于Epstein-Barr病毒（EBV）的质粒载体，并与阳离子聚合物或阳离子脂质组合。将EBV-质粒/聚酰胺-胺树枝状聚合物复合物注射入严重联合免疫缺陷小鼠的PC-3衍生肿瘤中，可在肿瘤中获得标记基因的大量表达，其表达水平比常规质粒载体/树枝状聚合物高8倍以上。由于大多数PC细胞表面表达凋亡信号分子Fas（Apo-1/CD 95），因此将Fas配体（FasL）基因导入PC细胞以杀伤肿瘤细胞。用pGEG体外转染。FasL（一种带有FasL基因的EBV质粒）显著降低PC细胞的活力，随后PC细胞发生凋亡。PC瘤内注射pGEG、FasL可明显抑制移植瘤的生长，TUNEL染色和电镜观察显示移植瘤具有典型的细胞凋亡特征。当pGEG. FasL转移伴随顺铂全身给药，肿瘤抑制更加显著，导致动物存活延长。以EBV为载体的质粒/阳离子大分子复合物转染FasL基因可能是一种实用的抗PC治疗策略。
To accomplish efficient nonviral gene therapy against prostate cancer (PC), Epstein-Barr virus (EBV)-based plasmid vectors containing EBNA 1 gene and oriP were employed and combined with a cationic polymer or cationic lipid. When EBV-plasmid/poly-amidoamine dendrimer complex was injected into PC-3-derived tumors established in severe combined immunodeficiency mice, a considerable expression of marker gene was obtained in the tumors, and the expression level was more than eight-fold higher than that achieved by conventional plasmid vector/dendrimer. Since most PC cells express the apoptotic signal molecule Fas (Apo-1/CD95) on their surface, Fas ligand (FasL) gene was transferred into PC cells to kill the tumor cells. In vitro transfection with pGEG. FasL (an EBV-plasmid with the FasL gene) significantly reduced the viability of PC cells, which subsequently underwent apoptosis. Intratumoral injections of pGEG.FasL into PC induced significant growth suppression of the xenograft tumors, in which typical characteristics of apoptosis were demonstrated by TUNEL staining and electron microscopic observations. When pGEG. FasL transfer was accompanied by systemic administrations of cisplatin, the tumors were inhibited even more remarkably, leading to prolonged survival of the animals. FasL gene transfection by means of EBV-based plasmid/cationic macromolecule complexes may provide a practical therapeutic strategy against PC.