Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth J A, Fang B
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 2000 Oct 1;60(19):5359-64.
Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly active in immortalized cells and >85% of human cancers but is quiescent in most normal somatic cells. To test the feasibility of using the hTERT promoter to induce tumor-specific transgene expression in cancer gene therapy, we constructed an adenoviral vector expressing a LacZ reporter gene driven by the hTERT core promoter and evaluated its activity in vitro and in vivo. The hTERT promoter could drive high-level expression of LacZ in tumor cells but not in normal cells and normal mouse tissues. Using a binary adenoviral system that can induce Bax gene expression, we showed that induction of the Bax gene expression via the hTERT promoter elicited tumor-specific apoptosis in vitro, suppressed tumor growth in nude mice, and prevented the toxicity of the Bax gene in vitro and in vivo. Thus, the hTERT promoter is apparently a strong and tumor-selective promoter with potential application in targeted cancer gene therapy.
人端粒酶逆转录酶（hTERT）是端粒酶的催化亚基，在永生化细胞和超过85%的人类癌症中高度活跃，但在大多数正常体细胞中处于静止状态。为了测试在癌症基因治疗中使用hTERT启动子诱导肿瘤特异性转基因表达的可行性，我们构建了一种腺病毒载体，该载体表达由hTERT核心启动子驱动的LacZ报告基因，并在体外和体内评估了其活性。hTERT启动子可驱动肿瘤细胞中LacZ的高水平表达，但在正常细胞和正常小鼠组织中则不然。使用一种可诱导Bax基因表达的二元腺病毒系统，我们发现通过hTERT启动子诱导Bax基因表达可在体外引发肿瘤特异性凋亡，抑制裸鼠体内肿瘤生长，并在体外和体内防止Bax基因的毒性。因此，hTERT启动子显然是一种强大的肿瘤选择性启动子，在靶向癌症基因治疗中具有潜在应用价值。
