Saretzki G, Ludwig A, von Zglinicki T, Runnebaum I B
Department of Gynecology, University Hospital, Freiburg, Germany.
Cancer Gene Ther. 2001 Oct;8(10):827-34. doi: 10.1038/sj.cgt.7700383.
Telomerase is a promising target for human cancer gene therapy. Its inhibition allows telomere shortening to occur in cancer cells, which in turn is thought to trigger delayed senescence and/or apoptosis. We tested whether telomerase inhibition might have additional, immediate effects on tumor cell growth. Ovarian cancer cell lines with widely differing telomere lengths were efficiently transduced with an adenovirus expressing a ribozyme directed against the T motif of the catalytic subunit of human telomerase, hTERT. Three days after transduction, telomerase activity was significantly reduced and massive cell loss was induced in mass cultures from all four ovarian cancer cell lines tested, whereas transduction of telomerase-negative human fibroblasts did not attenuate their growth. The kinetics of induction of cell death in cancer cells was not significantly dependent on telomere length, and telomeres did not shorten measurably before the onset of apoptosis. The data suggest the existence of a "fast-track" mechanism by which diminution of telomerase can interfere with cancer cell growth and induce cell death, presumably by apoptosis. This phenomenon might be a consequence of the telomere capping function provided by telomerase in tumor cells. Uncapping of telomeres by ribozyme-mediated inhibition of telomerase bears therapeutic potential for ovarian cancer.
端粒酶是人类癌症基因治疗中一个很有前景的靶点。对其进行抑制可使癌细胞中的端粒缩短，进而被认为会引发延迟性衰老和/或细胞凋亡。我们测试了抑制端粒酶是否可能对肿瘤细胞生长产生额外的即时效应。用一种表达针对人端粒酶催化亚基hTERT的T基序的核酶的腺病毒有效地转导了端粒长度差异很大的卵巢癌细胞系。转导三天后，在所有测试的四种卵巢癌细胞系的大规模培养物中，端粒酶活性显著降低，并诱导了大量细胞死亡，而端粒酶阴性的人成纤维细胞的转导并未减弱其生长。癌细胞中细胞死亡诱导的动力学并不显著依赖于端粒长度，并且在细胞凋亡开始之前端粒没有明显缩短。数据表明存在一种“快速通道”机制，通过该机制端粒酶的减少可干扰癌细胞生长并诱导细胞死亡，推测是通过细胞凋亡。这种现象可能是端粒酶在肿瘤细胞中提供的端粒封端功能的结果。通过核酶介导的端粒酶抑制使端粒去封端具有卵巢癌治疗潜力。
