Delwar Zahid M, Liu Guoyu, Kuo Yvonne, Lee Cleo, Bu Luke, Rennie Paul S, Jia William W
Experimental Medicine Program, Department of Medicine, University of British Columbia, Vancouver, Canada.
Department of Surgery, University of British Columbia, Vancouver, Canada.
Oncotarget. 2016 May 10;7(19):28658-69. doi: 10.18632/oncotarget.8637.
Oncolytic herpes simplex virus type 1 (oHSV-1) therapy is an emerging treatment modality that selectively destroys cancer. Here we report use of a glioma specific HSV-1 amplicon virus (SU4-124 HSV-1) to selectively target tumour cells. To achieve transcriptional regulation of the SU4-124 HSV-1 virus, the promoter for the essential HSV-1 gene ICP4 was replaced with a tumour specific survivin promoter. Translational regulation was achieved by incorporating 5 copies of microRNA 124 target sequences into the 3'UTR of the ICP4 gene. Additionally, a 5'UTR of rat fibroblast growth factor -2 was added in front of the viral ICP4 gene open reading frame. Our results confirmed enhanced expression of survivin and eIF4E in different glioma cells and increased micro-RNA124 expression in normal human and mouse brain tissue. SU4-124 HSV-1 had an increased ICP4 expression and virus replication in different glioma cells compared to normal neuronal cells. SU4-124 HSV-1 exerted a strong antitumour effect against a panel of glioma cell lines. Intracranial injection of SU4-124 HSV-1 did not reveal any sign of toxicity on day 15 after the injection. Moreover, a significantly enhanced antitumour effect with the intratumourally injected SU4-124 HSV-1 virus was demonstrated in mice bearing human glioma U87 tumours, whereas viral DNA was almost undetectable in normal organs. Our study indicates that incorporation of multiple cancer-specific regulators in an HSV-1 system significantly enhances both cancer specificity and oncolytic activity.
1型溶瘤单纯疱疹病毒（oHSV-1）疗法是一种新兴的治疗方式，可选择性地破坏癌细胞。在此，我们报告了使用一种胶质瘤特异性HSV-1扩增病毒（SU4-124 HSV-1）来选择性靶向肿瘤细胞。为实现SU4-124 HSV-1病毒的转录调控，将必需的HSV-1基因ICP4的启动子替换为肿瘤特异性生存素启动子。通过将5个拷贝的微小RNA 124靶序列整合到ICP4基因的3'非翻译区来实现翻译调控。此外，在病毒ICP4基因开放阅读框前添加了大鼠成纤维细胞生长因子-2的5'非翻译区。我们的结果证实了生存素和真核翻译起始因子4E（eIF4E）在不同胶质瘤细胞中的表达增强，以及在正常人和小鼠脑组织中微小RNA124表达增加。与正常神经元细胞相比，SU4-124 HSV-1在不同胶质瘤细胞中ICP4表达增加且病毒复制增强。SU4-124 HSV-1对一组胶质瘤细胞系具有强大的抗肿瘤作用。注射SU4-124 HSV-1后第15天，颅内注射未显示任何毒性迹象。此外，在携带人胶质瘤U87肿瘤的小鼠中，瘤内注射SU4-124 HSV-1病毒显示出显著增强的抗肿瘤作用，而在正常器官中几乎检测不到病毒DNA。我们的研究表明，在HSV-1系统中整合多种癌症特异性调节因子可显著增强癌症特异性和溶瘤活性。
