Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo

Since the up-regulated expression of human telomerase reverse transcriptase (hTERT) is a hallmark of alltypes of NSCLC, we chose hTERT promoter to transcriptionally control E1A gene expression to obtain adenoviral replication in NSCLC. In order to further enhance anti-tumor effect of this oncolytic adenoviral vector, we inserted a 'suicide gene' i.e. Herpes Simplex Virus Thymidine Kinase (HSV-TK) into oncolytic adenoviral vector to engineer a novel armed oncolytic adenoviral vector 'Ad.hTERT-E1A-TK'.Ad.hTERT-E1A-TK efficiently killed different types of tumor cells including two types of NSCLC cells in vitro, causing no damage to normal primary fibroblasts. Furthermore, Ad.hTERT-E1A-TK infection combined with administration of prodrug gancyclovir (GCV) resulted in more potent cytotoxicity on NSCLC cells, and synergistically suppressed human NSCLC tumor growth in nude mice.The results from this study showed that Ad.hTERT-E1A-TK/GCV could be a potent but safe anti-tumor strategy for NSCLC biotherapy.Lung cancer is one of the most common malignant neoplasm diseases in which non-small cell lung cancer (NSCLC) constitutes 80%-85% of all lung cancers [1]. Due to the lack of early diagnostic methods, most of NSCLC cases are diagnosed at the late phase and patients usually lose the opportunity of surgical treatment. Despite the fact that chemotherapy and radiotherapy provides many options to treat NSCLC, a survival plateau has been reached and its mortality is still in the first place in cancer patients [2,3]. Therefore it is urgent to explore other treatment strategies. Molecule targeting therapy represents a rapidly growing cancer treatment strategy and several drugs have been proven effective in many preclinical and clinical setting [4,5]. Suicide gene therapy possesses the advantage of molecule targeting strategies because the suicide gene functions in the transformed tumor cells and then selectively kills transformed tumor cells and their surrounding cells via bystander