Lethal mutagenesis: targeting the mutator phenotype in cancer.

Lethal mutagenesis: targeting the mutator phenotype in cancer.
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DOI:
10.1016/j.semcancer.2010.10.005
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发表时间:
2010-10
影响因子:
14.5
通讯作者:
Loeb LA
Loeb LA
中科院分区:
医学1区
文献类型:
--
作者:
Fox EJ;Loeb LA

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癌症和RNA病毒的进化有许多相似之处。两者都利用高水平的基因型多样性来实现广泛的表型可塑性,从而促进快速适应。为了积累大量的突变,我们提出癌症表达一种突变表型。与癌细胞类似,许多病毒群体通过以低保真度复制其基因组,携带大量突变负荷。由于高水平的突变是潜在有害的,因此将病毒突变频率阈值设定在一个水平,低于该水平,病毒群体在传统突变-选择平衡中平衡,高于该水平,群体不再存活,即,人口经历了一场错误灾难。因此,病毒群体对突变负荷的进一步增加是敏感的,并且最近这种现象已经通过被称为致死诱变的概念在治疗上被利用。在这里,我们回顾了致死性诱变治疗艾滋病毒的应用,并讨论如何致死性诱变可能代表一种新的治疗方法,用于治疗实体癌。
The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Consequently viral populations are susceptible to further increases in mutation load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers.
DOI: 10.1038/nature08989
发表时间: 2010-04-15
期刊: Nature
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