Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer.
Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer.
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DOI：
10.1158/1078-0432.ccr-10-0526
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发表时间：
2010-09-15
期刊：
影响因子：
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通讯作者：
O'Shaughnessy J
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文献类型：
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作者：
Annunziata CM;O'Shaughnessy J
癌症化疗利用修复 DNA 损伤的局限性来杀死增殖的恶性细胞。最近的证据表明，组织类型内和组织类型之间的癌症在 DNA 修复途径中存在特定缺陷，并且这些缺陷可能导致对各类细胞毒性药物的敏感性和耐药性。聚 ADP 核糖聚合酶 (PARP) 和 BRCA 蛋白是 DNA 链断裂修复的核心，当存在缺陷时，会导致容易出错的 DNA 修复所引入的突变积累。乳腺癌、卵巢癌和其他癌症是在 BRCA 缺陷的情况下发生的，这些癌症可能对诱导 DNA 链断裂的细胞毒性药物以及 PARP 活性抑制剂更敏感。最近的一系列临床试验测试了 PARP 抑制剂是否可以在 BRCA 通路缺陷的肿瘤中实现合成致死作用。未来的研究必须寻求识别散发性癌症，这些癌症具有基因组不稳定性，导致对诱导额外且致命的 DNA 损伤的药物敏感。
Cancer chemotherapy exploits limitations in repairing DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Poly-ADP ribose polymerase (PARP) and BRCA proteins are central to the repair of DNA strand breaks and, when defective, lead to the accumulation of mutations introduced by error-prone DNA repair. Breast, ovarian and other cancers develop in the setting of BRCA deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in BRCA-pathway-deficient tumors. Future studies must seek to identify sporadic cancers that harbor genomic instability rendering susceptibility to agents that induce additional and lethal DNA damage.