Department of Oncology and Haematology, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy.
Medical Affair Astrazeneca Lab Italy, 20080 Basiglio (MI), Italy.
Curr Cancer Drug Targets. 2018;18(9):877-893. doi: 10.2174/1568009618666180308104646.
The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologousrecombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCAmutation carriers leads to the persistence of DNA damage usually repaired by the homologousrecombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in "BRCAness" ovarian tumors, and in BRCA-related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice.
晚期卵巢癌的标准治疗方法是以最大限度地进行肿瘤细胞减灭术为基础，联合紫杉烷类和铂类药物的化疗方案，可能还需要联合贝伐珠单抗和（或）腹腔内化疗。尽管采用了这种综合性的治疗策略，仍有近 75%的患者复发或进展，因此需要二线治疗，此时患者对化疗的敏感性降低，预后更差。在过去十年中，人们在 BRCA 相关性卵巢癌中开发了一种改善这些患者预后的方法。BRCA 基因之一的突变导致同源重组 DNA 修复受损，从而导致促进致癌作用的遗传异常。有趣的是，这种缺陷已被聚 ADP-核糖聚合酶（PARP）抑制剂的引入所利用，以提供对特定癌细胞的细胞毒性。特别地，在 BRCA 突变携带者中抑制 PARP 会导致同源重组系统通常修复的 DNA 损伤持续存在，导致细胞周期停滞，从而引发细胞凋亡。尽管作用机制不同，但 PARP 抑制剂在“BRCA 样”卵巢肿瘤和除卵巢外的 BRCA 相关肿瘤中也显示出活性，这表明这些药物可能具有活性，而与 BRCA 突变状态或起源部位无关。本文旨在描述促使 PARP 抑制剂的开发和研究的主要证据，并讨论其在我们日常临床实践中的主要意义。
