Herbert B, Pitts A E, Baker S I, Hamilton S E, Wright W E, Shay J W, Corey D R
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA.
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14276-81. doi: 10.1073/pnas.96.25.14276.
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.
端粒酶活性与人类肿瘤之间的相关性引发了这样一种假说，即肿瘤生长需要端粒酶重新激活，并且端粒酶抑制剂代表了一类化疗药物。在此，我们研究了在人类细胞内抑制端粒酶的效果。肽核酸和2'-O-甲基RNA寡聚物抑制端粒酶，导致端粒逐渐缩短，并使永生化的人类乳腺上皮细胞凋亡频率增加，直至无细胞存活。端粒缩短是可逆的：如果终止抑制剂的添加，端粒会恢复其初始长度。我们的结果证实端粒酶是抗癌药物研发的一个靶点，并为成功药物无论化学类型如何都需要具备的特性提供了一般性见解。化学结构相似的寡核苷酸正在进行临床试验，并且具有特征明确的药代动力学，这使得我们所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。
