New treatment option for ovarian cancer: PARP inhibitors.
New treatment option for ovarian cancer: PARP inhibitors.
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DOI：
10.1186/s40661-016-0024-7
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Chen AP
中科院分区：
文献类型：
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作者：
Meehan RS;Chen AP
多聚腺苷二磷酸核糖聚合酶（Poly（ADP-ribose）polymerase，PARP）是50多年前由Mandel首先描述的一类参与DNA损伤反应的蛋白酶家族，它通过识别单链DNA断裂（single-strand DNA break，ssDNA），进而影响DNA修复而发挥作用。双链DNA（dsDNA）断裂可以通过两种不同途径之一修复：同源重组（HR）或非同源末端连接（NHEJ）。同源重组发生在细胞周期的G2或M期，此时姐妹染色单体可用作修复模板。由于模板是可用的，HR是一种高保真、无错误的DNA修复形式。NHEJ没有模板，DNA被修剪和连接，这是一个非常容易出错的修复过程，可能导致遗传不稳定。利用这些机制导致PARP抑制剂的开发，其想法是利用合成致死性，其中两种缺陷各自对细胞结果没有影响，当组合时，作为BRCA缺陷患者中的单一药剂或作为化疗/放疗组合以抑制ssDNA修复时变得致命。奥拉帕尼最近在美国和欧洲批准用于BRCA缺陷卵巢癌患者，为卵巢癌患者开辟了一种全新的治疗选择。本文将讨论不同的PARP抑制剂的发展和这类药物在未来的潜在用途。
Poly(ADP-ribose) polymerase (PARP), which was first described over 50 years ago by Mandel, are a family of protein enzymes involved in DNA damage response and works by recognizing the single-strand DNA break (ssDNA) and then effecting DNA repair. A double-strand DNA (dsDNA) break can be repaired by one of two different pathways: homologous recombination (HR) or non-homologous end joining (NHEJ). Homologous recombination occurs in the G2 or M phase of the cell cycle when a sister chromatid is available to use as a template for repair. Because a template is available, HR is a high fidelity, error-free form of DNA repair. With NHEJ there is not a template and the DNA is trimmed and ligated which is a very error-prone process of repair which can lead to genetic instability. Exploiting these mechanism led to development of PARP inhibitors with the idea of utilizing synthetic lethality, where two deficiencies each having no effect on the cellular outcome become lethal when combined, as single agent in BRCA deficient patients or as chemotherapy/radiotherapy combinations to inhibit ssDNA repair. The recent approval of olaparib in BRCA deficient ovarian cancer patients in US and Europe has opened up a whole new treatment option for ovarian cancer patients. This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future.