文章：

抗癌治疗背景下的合成致死概念

The Concept of Synthetic Lethality in the Context of Anticancer Therapy

原文发布日期：2005-08-19

DOI: 10.1038/nrc1691

类型: Review Article

开放获取: 否

要点：

1. Many chemicals kill cancer cells but their toxicity to normal cells limits their usefulness as anticancer drugs.
2. Epigenetic and genetic alterations within cancer cells, as well as changes in their microenvironment, might increase their requirement for a particular molecular target (or targets) relative to normal cells, creating an opportunity for selectivity.
3. Two genes are synthetic lethal if mutation of either gene alone is compatible with viability but mutation of both leads to death. Inhibiting the products of genes that are synthetic lethal to cancer-causing mutations should, by definition, kill cells that harbour such mutations, while sparing normal cells.
4. Most drugs induce a loss-of-function phenotype. High-throughput screens using matched cell-line pairs and chemical libraries allow the identification of chemicals that inhibit or kill cells in a genotype-specific manner. The challenge in this setting is to identify the relevant target (or targets) of compounds that score positively.
5. Genome-wide RNA-interference screens can now be used to identify synthetic lethal interactions in cells that are derived from higher eukaryotes, including humans.
6. Gene–gene interactions, including synthetic lethal interactions that are discovered in cell-culture experiments, will ultimately need to be validated in vivo. It seems likely that some gene–gene interactions will be highly robust, whereas others might be valid only in specific cells or under specific experimental conditions.

要点翻译：

1. T细胞白血病/淋巴瘤1（TCL1）基因家族在人类中包含三个基因，在小鼠中包含七个基因，这些基因编码小型细胞内β-桶状蛋白。已知人类TCL1家族成员能够结合并增强AKT激酶活性，从而调控来自环境的信号传导。
2. TCL1家族成员的正常表达似乎主要局限于早期胚胎发生、生殖细胞、特定胎儿及成人组织以及前体/未成熟T淋巴细胞和B淋巴细胞。
3. T细胞中因染色体重排或B细胞中可能因EB病毒感染或异常沉默导致的TCL1家族基因表达失调，会增强细胞增殖和存活，并在长潜伏期后引发细胞转化。
4. 异常表达TCL1基因的转基因小鼠为成熟人类淋巴恶性肿瘤（包括T细胞幼淋巴细胞白血病、伯基特淋巴瘤、弥漫性大B细胞淋巴瘤、罕见滤泡性淋巴瘤和B细胞慢性淋巴细胞白血病）提供了独特模型，这些疾病在其他遗传、病毒或环境干预后未曾出现。
5. TCL1介导转化的精确机制尚未明确。细胞质及细胞核中可能存在与AKT相关的靶蛋白。为解析TCL1蛋白如何引发癌症，关键需要明确TCL1家族基因的调控与失调机制，理解其不依赖于AKT的潜在效应，发现恶性转化所需的协同改变，并确定其在淋巴细胞以外的转化活性。

英文摘要：

Two genes are synthetic lethal if mutation of either alone is compatible with viability but mutation of both leads to death. So, targeting a gene that is synthetic lethal to a cancer-relevant mutation should kill only cancer cells and spare normal cells. Synthetic lethality therefore provides a conceptual framework for the development of cancer-specific cytotoxic agents. This paradigm has not been exploited in the past because there were no robust methods for systematically identifying synthetic lethal genes. This is changing as a result of the increased availability of chemical and genetic tools for perturbing gene function in somatic cells.

摘要翻译： 

两个基因若单独突变任一均不影响细胞存活，但同时突变则导致死亡，即称为合成致死。因此，针对与癌症相关突变呈合成致死关系的基因进行靶向，应仅杀死癌细胞而不损伤正常细胞。合成致死由此为开发癌症特异性细胞毒药物提供了理论框架。过去因缺乏系统鉴定合成致死基因的有效方法，这一策略未被充分利用；随着在体细胞中干扰基因功能的化学与遗传工具日益丰富，这一局面正在改变。

原文链接：

The Concept of Synthetic Lethality in the Context of Anticancer Therapy