Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: Preclinical evaluation of chemovirotherapy
Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: Preclinical evaluation of chemovirotherapy
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DOI：
10.1002/ijc.21846
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发表时间：
2006-07-15
影响因子：
6.4
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Fujiwara, Toshiya;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
溶瘤腺病毒正在被开发为新型抗癌疗法，目前正在进行临床试验。我们之前证明，端粒酶特异性复制腺病毒（Telomelysin：OBP-301）能够有效杀死人类肿瘤细胞，其中人端粒酶逆转录酶（hTERT）启动子调节病毒复制。我们进一步构建了OBP-401（Telomelysin-GFP），它在E3区巨细胞病毒启动子的控制下表达绿色荧光蛋白（GFP）报告基因，以监测病毒分布。在这里，我们研究了 OBP-401 单药治疗以及 OBP-401 与化疗药物联合治疗的可行性。单独感染 OBP-401 或随后使用化疗药物多西紫杉醇（泰索帝）治疗，可在源自不同器官（肺、结肠、食道、胃、肝脏和前列腺）的各种人类癌细胞系中产生显着的体外细胞毒性和 GFP 表达，尽管抗肿瘤作用的程度因细胞类型而异。其他化疗药物如长春瑞滨 (Navelbine) 和 SN38（伊立替康的强效活性代谢物）与 OBP-401 联合使用也能抑制人类癌细胞的生长。实时定量PCR分析表明多西紫杉醇不影响病毒复制。为了进行体内评估，异种移植 H1299 人肺肿瘤的 nu/nu 小鼠接受瘤内注射 OBP-401 和腹膜内施用多西紫杉醇。植入肿瘤生长的分析显示出显着的治疗协同作用，尽管单独的 OBP-401 和单独的多西紫杉醇显示出对肿瘤生长的适度抑制。因此，OBP-401与多西紫杉醇联合有效增强了体外和体内的抗肿瘤功效，其结果对人类癌症的肿瘤特异性溶瘤化学病毒治疗具有重要意义。 (c) 2006 Wiley-Liss, Inc.
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. (c) 2006 Wiley-Liss, Inc.