PARP inhibitors as potential therapeutic agents for various cancers: focus on niraparib and its first global approval for maintenance therapy of gynecologic cancers.
PARP inhibitors as potential therapeutic agents for various cancers: focus on niraparib and its first global approval for maintenance therapy of gynecologic cancers.
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DOI：
10.1186/s40661-017-0055-8
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Edessa D
中科院分区：
文献类型：
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作者：
Sisay M;Edessa D
聚ADP核糖聚合酶（Poly（ADP-ribose）polymerases，PARP）是一类重要的核蛋白家族，与DNA损伤修复密切相关。在PARP家族中，研究最多的是PARP 1、PARP 2和PARP 3。PARP 1是PARP系列中最丰富的核酶。这些酶主要参与作为主要单链断裂（SSB）修复机制之一的碱基切除修复。作为双链，DNA在PARP的帮助下参与亚致死SSB的修复。此外，通过姐妹染色单体，DNA也可以通过无错误同源重组或易错非同源末端连接修复双链断裂。对于有效的同源重组修复，DNA需要编码BRCA 1/2的功能性杂合乳腺癌基因（BRCA）。目前，PARP抑制剂的开发已成为肿瘤化疗的突破性进展之一。2017年3月，美国食品药品监督管理局（FDA）批准Niraparib用于对既往铂类化疗敏感的复发性妇科癌症（上皮性卵巢癌、原发性腹膜癌和输卵管癌）的维持治疗，无论BRCA突变和同源重组缺陷状态如何。它是继olaparib和rucaparib之后获得FDA批准的第三种此类药物，也是第一个全球批准用于上述癌症维持治疗的药物。Niraparib优先阻断PARP 1和PARP 2酶。Niraparib的每日耐受剂量为300 mg，高于该剂量时观察到剂量限制性3级和4级毒性。与人源化抗体pembrolizumab组合，也正在研究用于患有三阴性乳腺癌的患者。总的来说，有几项正在进行的临床试验正在研究这种药物对各种恶性肿瘤的临床疗效和安全性，以及其他药代动力学和药效学特征。
Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining. For effective homologous recombination repair, DNA requires functional heterozygous breast cancer genes (BRCA) which encode BRCA1/2. Currently, the development of PARP inhibitors has been one of the promising breakthroughs for cancer chemotherapy. In March 2017, the United States Food and Drug Administration (FDA) approved niraparib for maintenance therapy of recurrent gynecologic cancers (epithelial ovarian, primary peritoneal and fallopian tube carcinomas) which are sensitive to previous platinum based chemotherapy irrespective of BRCA mutation and homologous recombination deficiency status. It is the third drug in this class to receive FDA approval, following olaparib and rucaparib and is the first global approval for maintenance therapy of the aforementioned cancers. Niraparib preferentially blocks both PARP1 and PARP2 enzymes. The daily tolerated dose of niraparib is 300 mg, above which dose limiting grade 3 and 4 toxicities were observed. In combination with humanized antibody, pembrolizumab, it is also under investigation for those patients who have triple negative breast cancer. By and large, there are several clinical trials that are underway investigating clinical efficacy and safety, as well as other pharmacokinetic and pharmacodynamic profiles of this drug for various malignancies.