Zou Weiguo, Luo Chunxia, Zhang Zilai, Liu Jing, Gu Jingfa, Pei Zifei, Qian Cheng, Liu Xinyuan
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
Oncogene. 2004 Jan 15;23(2):457-64. doi: 10.1038/sj.onc.1207033.
Telomerase is a therapeutic target for cancer. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionaly upregulated exclusively in about 90% of cancer cells. Previous studies have demonstrated that hTERT promoter can control the expression of exogenous genes to the telomerase-positive cancer cells, thus hTERT promoter is an excellent candidate for generating cancer-specific oncolytic adenovirus. In this study, we devised a novel oncolytic adenovirus (Ad.TERT) by replacing the normal E1A regulatory elements with hTERT promoter. Ad.TERT displays cancer-specific E1A expression, virus replication and cytolysis in in vitro experiments. In animal experiments, intratumoral administration of Ad.TERT demonstrates potent antitumoral efficacy at least in two xenograft models (Bcap37 and BEL7404). Ad.TERT was targeted by the telomerase activity in cancer cells and has potent antitumoral efficacy in vivo, and since telomerase activity is a wide-ranged tumor marker, Ad.TERT could be a powerful therapeutic agent for a variety of cancers.
端粒酶是癌症的一个治疗靶点。人端粒酶逆转录酶（hTERT）是端粒酶的催化亚基，仅在约90%的癌细胞中发生转录上调。先前的研究表明，hTERT启动子可将外源基因的表达控制到端粒酶阳性癌细胞中，因此hTERT启动子是生成癌症特异性溶瘤腺病毒的极佳候选者。在本研究中，我们通过用hTERT启动子替换正常的E1A调控元件，设计了一种新型溶瘤腺病毒（Ad.TERT）。在体外实验中，Ad.TERT表现出癌症特异性的E1A表达、病毒复制和细胞溶解。在动物实验中，瘤内注射Ad.TERT至少在两种异种移植模型（Bcap37和BEL7404）中显示出强大的抗肿瘤功效。Ad.TERT被癌细胞中的端粒酶活性靶向，并且在体内具有强大的抗肿瘤功效，而且由于端粒酶活性是一种广泛的肿瘤标志物，Ad.TERT可能成为治疗多种癌症的有力治疗药物。
