Targeting the limitless replicative potential of cancer: The telomerase/telomere pathway
Targeting the limitless replicative potential of cancer: The telomerase/telomere pathway
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DOI：
10.1158/1078-0432.ccr-07-0422
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发表时间：
2007-09-01
影响因子：
11.5
通讯作者：
Kelland, Lloyd
中科院分区：
文献类型：
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作者：
Kelland, Lloyd
端粒DNA的维持是肿瘤具有无限复制潜力的基础，这是癌症的标志之一。端粒的长度和结构是由逆转录酶、端粒酶和一种多蛋白端粒复合体来维持的。绝大多数肿瘤的端粒酶活性升高，与正常组织相比，肿瘤组织的端粒严重缩短，从而为针对端粒酶/端粒途径进行广谱癌症治疗提供了令人信服的理论基础。这一策略得到了各种基于遗传的目标验证研究的支持。端粒酶抑制剂和端粒相互作用分子在无毒剂量下对小鼠各种人类肿瘤移植瘤都显示出单独的抗肿瘤活性。这些翻译上的进展导致了第一种抗端粒酶药物，基于寡核苷酸的靶向端粒酶RNA模板的GRN163L，进入临床评估。其他的翻译方法，如使用G-四链配体靶向端粒，应该会在不久的将来导致RHPS4等抗端粒药物进入临床。这些原型试验将在确定端粒酶/端粒途径在临床肿瘤学中的作用以及针对癌症无限复制潜力的药物是否会在癌症化疗中找到一席之地方面提供极其丰富的信息。
The maintenance of telomeric DNA underlies the ability of tumors to possess unlimited replicative potential, one of the hallmarks of cancer. Telomere length and structure are maintained by the reverse transcriptase telomerase and a multiprotein telomere complex termed shelterin. Telomerase activity is elevated in the vast majority of tumors, and telomeres are critically shortened in tumors versus normal tissues, thus providing a compelling rationale to target the telomerase/ telomere pathway for broad-spectrum cancer therapy. This strategy is supported by a variety of genetic-based target validation studies. Both telomerase inhibitors and telomere interactive molecules have shown stand-alone antitumor activity at nontoxic doses against a variety of human tumor xenografts in mice. These translational advances have resulted in the first antitelomerase agent, the oligonucleotide-based GRN163L targeting the telomerase RNA template, entering clinical evaluation. Additional translational approaches, such as targeting telomeres using G-quadruplex ligands, should result in antitelomere agents, such as RHPS4, entering the clinic in the near future. These prototype trials will be extremely informative in determining the role of the telomerase/telomere pathway in clinical oncology and, moreover, Whether drugs targeting the unlimited replicative potential of cancer will find a place in cancer chemotherapy.