Gu J, Andreeff M, Roth J A, Fang B
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Gene Ther. 2002 Jan;9(1):30-7. doi: 10.1038/sj.gt.3301619.
We recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression and selectively kills various human cancer cells both in vitro and in xenograft tumors. However, it remains unclear whether the hTERT promoter can be used to induce transgene expression in syngenic tumors in mice and whether Bax gene expression driven by the hTERT promoter will cause long-term, stem cell-related toxicity. To address these questions, we tested hTERT promoter-driven, adenovirus-mediated Bax transgene expression in an established syngenic mouse tumor model and its effects on tumor and normal murine tissues. The hTERT promoter was highly active in several murine tumor cell lines and a transformed cell line, but not in non-transformed and normal murine cell lines. The hTERT promoter induced tumor-specific Bax gene expression in mouse UV-2237m fibrosarcoma cells both in vitro and in vivo and suppressed syngenic tumor growth in immune-competent mice with no obvious acute or long-term toxic effects. Moreover, hTERT promoter-driven transgene expression in human CD34(+) bone marrow progenitor cells had effects similar to those observed in other normal human cells, suggesting that the hTERT promoter is much less active in CD34(+) cells than in tumor cells. Together, our data demonstrate that the hTERT promoter may allow the use of proapoptotic genes for cancer treatment without noticeable effects on progenitor cells.
我们最近发现，人端粒酶逆转录酶（hTERT）启动子可诱导肿瘤特异性Bax基因表达，并在体外和异种移植肿瘤中选择性杀死各种人类癌细胞。然而，hTERT启动子是否可用于诱导小鼠同基因肿瘤中的转基因表达，以及hTERT启动子驱动的Bax基因表达是否会导致长期的、与干细胞相关的毒性，仍不清楚。为了解决这些问题，我们在已建立的同基因小鼠肿瘤模型中测试了hTERT启动子驱动的、腺病毒介导的Bax转基因表达及其对肿瘤和正常小鼠组织的影响。hTERT启动子在几种小鼠肿瘤细胞系和一种转化细胞系中高度活跃，但在未转化的正常小鼠细胞系中不活跃。hTERT启动子在体外和体内均可诱导小鼠UV-2237m纤维肉瘤细胞中肿瘤特异性Bax基因表达，并抑制免疫健全小鼠的同基因肿瘤生长，且无明显的急性或长期毒性作用。此外，hTERT启动子驱动的转基因在人CD34(+)骨髓祖细胞中的表达与在其他正常人细胞中观察到的效果相似，这表明hTERT启动子在CD34(+)细胞中的活性远低于在肿瘤细胞中的活性。总之，我们的数据表明，hTERT启动子可能允许使用促凋亡基因进行癌症治疗，而对祖细胞无明显影响。
