Bochum Sylvia, Berger Stephanie, Martens Uwe M
Cancer Center Heilbronn-Franken, SLK-Kliniken Heilbronn GmbH and MOLIT Institute for Personalized Medicine, Am Gesundbrunnen 20-24, 74078, Heilbronn, Germany.
Recent Results Cancer Res. 2018;211:217-233. doi: 10.1007/978-3-319-91442-8_15.
Olaparib (Lynparza [AstraZeneca, Cambridge, UK], formerly referred to as AZD2281 or KU0059436) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor. It is rationally designed to act as a competitive inhibitor of NAD at the catalytic site of PARP1 and PARP2, both members of the PARP family of enzymes that are central to the repair of DNA single-strand breaks (SSBs) mediated via the base excision repair (BER) pathway. Inhibition of the BER pathway by olaparib leads to the accumulation of unrepaired SSBs, which leads to the formation of deleterious double-strand breaks (DSBs). In cells with an intact homologous recombination (HR) pathway, these DSBs can be repaired effectively. However, in tumors with homologous recombination repair deficiencies, olaparib causes synthetic lethality through the combination of two molecular events that are otherwise nonlethal when occurring in isolation. Olaparib is already approved for the treatment of patients with recurrent ovarian cancer and a BRCA mutation, and it has been shown to provide clinically meaningful benefits among such patients. It has also shown promising activity in patients with metastatic breast or prostate cancer and a germline BRCA mutation. Besides its usage as a single agent, olaparib can also act either as a chemo- and/or radiosensitizer, due to its ability to potentiate the cytotoxic effects of these therapeutic agents. However, a clear patient benefit for the latter application has not been demonstrated yet.
奥拉帕利（利普卓[阿斯利康，英国剑桥]，前称AZD2281或KU0059436）是一种口服聚（ADP - 核糖）聚合酶（PARP）抑制剂。它经过合理设计，可在PARP1和PARP2的催化位点作为烟酰胺腺嘌呤二核苷酸（NAD）的竞争性抑制剂，PARP1和PARP2是PARP酶家族的成员，对于通过碱基切除修复（BER）途径介导的DNA单链断裂（SSB）修复至关重要。奥拉帕利对BER途径的抑制导致未修复的SSB积累，进而导致有害双链断裂（DSB）的形成。在具有完整同源重组（HR）途径的细胞中，这些DSB可以有效修复。然而，在具有同源重组修复缺陷的肿瘤中，奥拉帕利通过两种分子事件的联合导致合成致死性，这两种事件单独发生时并不致命。奥拉帕利已被批准用于治疗复发性卵巢癌且伴有BRCA突变的患者，并且已证实在此类患者中可提供具有临床意义的益处。它在转移性乳腺癌或前列腺癌且伴有种系BRCA突变的患者中也显示出有前景的活性。除了作为单一药物使用外，奥拉帕利还可作为化疗和/或放疗增敏剂，因为它能够增强这些治疗药物的细胞毒性作用。然而，后者的应用对患者的确切益处尚未得到证实。
