the htert promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironmenthtert促进剂提高了抗肿瘤缺氧微环境下的溶瘤腺病毒的活动.pdf

The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment 1 1,2 1 1 1 1 Yuuri Hashimoto , Hiroshi Tazawa , Fuminori Teraishi , Toru Kojima , Yuichi Watanabe , Futoshi Uno , 1 3 1 1 Shuya Yano , Yasuo Urata , Shunsuke Kagawa , Toshiyoshi Fujiwara * 1 Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan, 2 Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan, 3 Oncolys BioPharma, Inc., Tokyo, Japan Abstract Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor- specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumul