Fujiwara Toshiya, Kagawa Shunsuke, Kishimoto Hiroyuki, Endo Yoshikatsu, Hioki Masayoshi, Ikeda Yoshihiro, Sakai Ryo, Urata Yasuo, Tanaka Noriaki, Fujiwara Toshiyoshi
Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Int J Cancer. 2006 Jul 15;119(2):432-40. doi: 10.1002/ijc.21846.
Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers.
溶瘤腺病毒正作为新型抗癌疗法进行研发，目前正处于临床试验阶段。我们之前证明，端粒酶特异性复制型腺病毒（Telomelysin：OBP - 301），其中人端粒酶逆转录酶（hTERT）启动子调节病毒复制，能有效杀死人肿瘤细胞。我们进一步构建了OBP - 401（Telomelysin - GFP），其在E3区域的巨细胞病毒启动子控制下表达绿色荧光蛋白（GFP）报告基因以监测病毒分布。在此，我们研究了OBP - 401单药治疗以及OBP - 401与化疗药物联合使用的可行性。单独感染OBP - 401或随后用化疗药物多西他赛（泰索帝）治疗，在源自不同器官（肺、结肠、食管、胃、肝和前列腺）的各种人癌细胞系中均产生了显著的体外细胞毒性和GFP表达，尽管抗肿瘤效果的程度在不同细胞类型中有所不同。其他化疗药物如长春瑞滨（诺维本）和SN38（伊立替康的强效活性代谢物）与OBP - 401联合也抑制了人癌细胞的生长。定量实时PCR分析表明多西他赛不影响病毒复制。为了进行体内评估，用H1299人肺肿瘤异种移植的裸鼠接受瘤内注射OBP - 401和腹腔内给予多西他赛。植入肿瘤生长分析显示出显著的治疗协同作用，尽管单独使用OBP - 401和单独使用多西他赛对肿瘤生长的抑制作用较小。因此，OBP - 401与多西他赛联合在体外和体内均能有效增强抗肿瘤疗效，这一结果对人类癌症的肿瘤特异性溶瘤化学病毒疗法具有重要意义。
