Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death
Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death
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DOI：
10.1073/pnas.96.25.14276
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发表时间：
1999-12-07
影响因子：
11.1
通讯作者：
Corey, DR
中科院分区：
文献类型：
--
作者：
Herbert, BS;Pitts, AE;Corey, DR
端粒酶活性与人类肿瘤之间的相关性导致了肿瘤生长需要端粒酶再活化的假设，并且端粒酶抑制剂代表了一类化疗剂。在此，我们研究了抑制人类细胞内端粒酶的影响。肽核酸和2 '-O-MeRNA寡聚体抑制端粒酶，导致进行性端粒缩短，并导致永生的人乳腺上皮细胞以增加的频率经历凋亡，直到没有细胞留下。端粒缩短是可逆的：如果终止抑制剂的添加，端粒恢复其初始长度。我们的研究结果验证了端粒酶作为抗癌药物发现的目标，并提供了一般的见解，成功的代理商将需要无论化学类型的属性。化学上相似的寡核苷酸正在临床试验中，并具有良好的药代动力学特征，使我们描述的抑制剂成为用于测试抗端粒酶化疗策略的实用先导化合物。
The correlation between telomerase activity and human tumors has led to the hypothesis that tumor growth requires reactivation of telomerase and that telomerase inhibitors represent a class of chemotherapeutic agents. Herein, we examine the effects of inhibition of telomerase inside human cells. Peptide nucleic acid and 2'-O-MeRNA oligomers inhibit telomerase, leading to progressive telomere shortening and causing immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain. Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths. Our results validate telomerase as a target for the discovery of anticancer drugs and supply general insights into the properties that successful agents will require regardless of chemical type. Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics, making the inhibitors we describe practical lead compounds for testing for an antitelomerase chemotherapeutic strategy.