In vivo inhibition of lung cancer by GRN163L:: A novel human telomerase inhibitor
In vivo inhibition of lung cancer by GRN163L:: A novel human telomerase inhibitor
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DOI：
10.1158/0008-5472.can-05-1215
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Shay, JW
中科院分区：
文献类型：
--
作者：
Dikmen, ZG;Gellert, GC;Shay, JW
端粒酶活性在正常细胞和肿瘤细胞中的不同调节为设计新型端粒酶抑制剂提供了理论基础。端粒酶复合体为抑制剂的开发提供了多个潜在的位点。GRN163L是一种端粒酶拮抗剂，是一种脂质修饰的13聚体寡核苷酸N3‘-和P5’-硫代磷酰胺，与端粒酶RNA的模板区域互补。我们利用表达荧光素酶报告基因的A549-荧光素酶(A549-Luc)评价了GRN163L在体外和体内的作用。GRN163L(1 mU/L)能有效抑制A549-Luc细胞的端粒酶活性，导致端粒进行性缩短。GRN163L处理也减少了软琼脂试验中的菌落形成。令人惊讶的是，仅用GRN163L处理一周后，A549-Luc细胞就不能在克隆中形成强大的克隆。效率测定，而错配对照化合物不起作用。最后，我们证明了GRN163L的体内治疗在预防异种移植动物模型肺转移方面是有效的。这些体外和体内数据支持GRN163L作为癌症治疗药物的发展。
Differential regulation of telomerase activity in normal and tumor cells provides a rationale for the design of new classes of telomerase inhibitors. The telomerase enzyme complex presents multiple potential sites for the development of inhibitors. GRN163L, a telomerase enzyme antagonist, is a lipid-modified 13-mer oligonucleotide N3' -> P5'-thiophosphoramidate, complementary to the template region of telomerase RNA (hTR). We evaluated both the in vitro and in vivo effects of GRN163L using A549-luciferase (A549-Luc) human lung cancer cells expressing a luciferase reporter. GRN163L (1 mu mol/L) effectively inhibits telomerase activity of A549-Luc cells, resulting in progressive telomere shortening. GRN163L treatment also reduces colony formation in soft agar assays. Surprisingly, after only I week of treatment with GRN163L, A549-Luc cells were unable to form robust colonies in the clonal. efficiency assay, whereas the mismatch control compound had no effect. Finally, we show that in vivo treatment with GRN163L is effective in preventing lung metastases in xenograft animal models. These in vitro and in vivo data support the development of GRN163L as a therapeutic for the treatment of cancer.