以hTR模板区为靶点的抗肿瘤药物设计策略

端粒酶几乎在所有的人类癌细胞中均异常表达,它的持久活性对肿瘤的增殖是必需的。因此,抑制端粒酶活性代表了一种新的癌症治疗机制。端粒酶全酶复合物有多处可以做为抑制剂的靶点,包括hTR、hTERT、引物锚定位点等。本文对以端粒酶RNA模板区为靶点的抗肿瘤药物设计策略进行了综述,包括对该区域进行点突变、使用反义寡核苷酸封闭模板区、改变端粒酶RNA空间构象等,并探讨了目前抑制端粒酶活性研究中存在的一些问题。

Targeting Template Region of Human Telomerase RNA for the Design of Anticancer Drugs

Telomeres,the genetic segments that appear at a chromosome's end.The ribomadeoprotein enzyme,telom- erase,uses RNA as a template to add a hexanucleodde to ends of replicating chromosomes resulting in stabilization of the telomere. The existence of telomerase can prevent the shortening of telomere.Measuring telomerase may be a new way to detect cancer.The initial connection between telomerase and cancer was established when most human tumors were found to express telomerase,but some normal tissues and cultures of normal cells did not,Telomerase activity was observed in over 85% of human primary malig- nancies.Therefore,inhibition of human telomerase activity would be a new strategy of cancer therapy.Many sites can be the tar- gets for inhibiting telomerase activity in human cancer cells,including hTR,hTERT,and primer anchor site,etc.Some investiga- tions showed that restraining hTR and hTERT at file same time cottld reduce telomerase activity better.Both of hTR and hTERT were critical for holoenzyme activity.In this paper,the design of anticancer drugs was summarized,which inhibits telomerase activi- ty by targeting the template region of human telomerase RNA,such as design of site-directed mutation in TR region,blocking out the TR region by antisense oligonucleodde,changing the three-dimensional conformation of telomerase RNA,etc.This article also discussed the problems in inhibiting telomerase activity research.