Telomerase-specific replication-selective virotherapy for human cancer
Telomerase-specific replication-selective virotherapy for human cancer
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DOI：
10.1158/1078-0432.ccr-1075-3
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发表时间：
2004-01-01
影响因子：
11.5
通讯作者：
Fujiwara, T
中科院分区：
文献类型：
--
作者：
Kawashima, T;Kagawa, S;Fujiwara, T
目的：复制选择性肿瘤特异性病毒为治疗肿瘤疾病提供了一种新方法。这些载体被设计为在肿瘤内选择性病毒增殖后诱导病毒介导的肿瘤细胞裂解。端粒酶激活被认为是癌变的关键步骤，其活性与人端粒酶逆转录酶（hTERT）的表达密切相关。我们研究了hTERT特异性复制能力的腺病毒对人类癌细胞的抗肿瘤作用。实验设计：我们构建了腺病毒5载体[肿瘤或端粒酶特异性复制能力的腺病毒（TRAD）]，其中hTERT启动子元件驱动与内部核糖体进入位点相连的E1A和E1B基因的表达，我们在体外和体内检查了人癌细胞中的选择性复制和抗肿瘤作用。体内结果：TRAD 在人类癌细胞中诱导选择性 E1A 和 E1B 表达，但在人类成纤维细胞等正常细胞中则不然。 TRAD 在一组人类癌细胞系中有效复制并诱导显着的细胞杀伤，而在缺乏端粒酶活性的正常人成纤维细胞中，复制和细胞毒性被高度减弱。在携带 s.c. 的 nu/nu 小鼠中在人肺肿瘤异种移植物中，瘤内注射TRAD可显着抑制肿瘤生长。尽管循环中存在 TRAD，但在肿瘤以外的组织中没有发现 TRAD 的证据。此外，还证明了 TRAD 在远处、非注射肿瘤中的复制。结论：我们的结果表明，hTERT 启动子赋予 TRAD 在人类癌细胞中选择性复制的能力，这一结果对人类癌症的治疗具有重要意义。
Purpose: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells.Experimental Design: We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo.Results: TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated.Conclusions: Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.