聚腺苷二磷酸核糖聚合酶抑制剂的临床研究进展

聚腺苷二磷酸核糖聚合酶(PARP)在癌症治疗中是一个非常重要的新靶点,通过碱基切除修复方式对单股DNA进行修复。近年来,新的协同放疗或化疗的PARP抑制剂已经进入了I、II或III期临床试验。众多的试验数据表明PARP抑制剂不仅可以作为化疗和放疗的增敏剂,而且在BRCA1和BRCA2基因突变的乳腺癌中可单独使用,选择性杀死DNA修复缺陷的癌细胞。本文综述了PARP抑制剂的作用机制和临床研究结果,评估了其不良反应和潜在药效,并提出了临床策略中可能存在的问题以及未来发展方向。     

PARP抑制剂在肿瘤中的治疗现状及展望

聚ADP-核糖聚合酶(PARP)抑制剂是治疗具有同源重组缺陷(HRD)肿瘤的靶向药物,其利用合成致死原理,针对特定的DNA修复途径,诱导BRCA1/2突变的肿瘤合成杀伤.目前,4种PARP抑制剂(奥拉帕利、卢卡帕利、尼拉帕利和他拉唑帕利)已获得美国食品药品监督管理局(FDA)批准,用于卵巢癌、转移性乳腺癌、晚期前列腺癌...     

治疗遗传性卵巢癌的新药——奥拉帕尼

奥拉帕尼(olaparib)是英国阿斯利康公司研发的一种多聚腺苷二磷酸酯核糖聚合酶强抑制剂,通过抑制基因同源重组缺陷,合成杀灭突变的癌细胞,可用于治疗有特异性DNA修复缺陷的癌症,是治疗2种易感基因BRCA1和BRCA2缺损的晚期卵巢癌药物。奥拉帕尼可以选择性杀死癌细胞而又不损害正常细胞,较之传统的化疗手段,其不良反应小得多。     

聚腺苷二磷酸核糖聚合酶的功能及其抑制剂潜在的临床应用

聚腺苷二磷酸核糖聚合酶（PARP）是人体重要的酶之一，参与染色质松弛、信号转录、DNA修复和细胞凋亡等生理过程。PABP过度激活则引起细胞坏死，从而介导多种病理过程。因此，抑制PARP可能会起到对某些疾病的治疗作用。本文综述了PARP的功能及PARP抑制剂的潜在临床应用。     

尼拉帕尼：聚腺苷二磷酸-核糖聚合酶抑制剂

尼拉帕尼（Niraparib,商品名Zejula^TM）是聚腺苷二磷酸-核糖聚合酶（PARP）的口服小分子抑制剂,PARP抑制是治疗由DNA修复基因（如BRCA1和BRCA2）特异性畸变引起的DNA修复机制缺陷的癌症的有效策略。尼拉帕尼于2017年3月在美国获批,维持治疗复发性上皮性卵巢癌、输卵管癌、原发性腹膜癌的成年患者,这些患者对铂类化疗有完全或部分反应,推荐剂量为口服300 mg/d,直到疾病发生恶化或产生无法接受的不良反应。临床研究结果表明该药可以延长患者的无恶化生存期,为治疗卵巢癌提供了有效和可靠的治疗手段。     

新型PARP抑制剂veliparib

肿瘤细胞能够激活自身DNA的损伤修复机制进行修复,从而导致其对抗肿瘤药物和放疗产生耐药性,而聚腺苷酸二磷酸核糖转移酶(poly ADP-ribose polymerase,PARP)是一种DNA修复酶,在DNA修复通路中起关键作用.veliparib 是一种新型高选择抑制PARP的苯并咪唑类化合物,体内外实验表明本品具有显著的抑制PARP活性的作用.在治疗转移性乳腺癌、结肠癌、转移性黑色素瘤和脑肿瘤方面已取得显著的效果,其与替莫唑胺联用治疗乳腺癌的研究即将进入Ⅲ期临床.     

FAMOUS研究：法莫替丁对阿司匹林所致胃肠粘膜损害的预防作用

背景及目的：抑制聚腺苷二磷酸酯核糖聚合酶（PARP）可致某些肿瘤细胞DNA修复障碍,促进肿瘤细胞凋亡,是治疗肿瘤的潜在方法,特别是对于BRCA1或BRCA2基因突变患者。Olaparib（AZD2281）为一种新型的口服PARP抑制剂,本研究对olaparib的有效性及安全性进行了临床评价。     

选择性作用于胰腺癌抑癌基因DPC4缺陷的分子

近年来，直接靶向作用于癌症的药物研究主要集中在抑制癌蛋白获得性突变。例如小分子化合物伊马替尼能靶向作用于慢性粒细胞白血病BCR-ABL癌蛋白及其他相关的酪氨酸激酶。尽管功能缺失突变在癌症发展中发挥举足轻重的作用，但靶向作用于肿瘤抑制基因中功能缺失突变基因，从而恢复其功能的研究甚少。最近有研究表明，乳腺癌BRCA1或BRCA2抑癌基因缺陷细胞对DNA损伤修复酶多聚（ADP-核糖）聚合酶（PARP）抑制剂敏感。     

PARP-1抑制剂和BRCA基因在乳腺癌治疗中的研究进展

多腺苷二磷酸核糖聚合酶-1[poly(ADP-ribose)polymerases-1,PARP-1]和BRCA在DNA单链和双链修复途径中起着至关重要的作用。研究表明,根据"合成致死"机制,通过抑制PARP-1活性,可以导致BRCA-1/2缺陷细胞DNA损伤修复的障碍,最终增强肿瘤细胞对放化疗的敏感性,因此以PARP-1和BRCA为靶点联合用药,或者在BRCA1和BRCA2基因突变的乳腺癌中使用PARP-1抑制剂,选择性杀死DNA修复缺陷的癌细胞,均显示出惊人的抗肿瘤效果。综述了联合PARP-1抑制剂和BRCA基因在乳腺癌放射治疗中的作用机制和临床研究结果,提出了临床策略中可能存在的问题以及未来发展方向。     

PARP抑制剂在BRCA胚系突变乳腺癌治疗中的研究进展

聚腺苷二磷酸核糖聚合酶(PARP)抑制剂是一种新型的小分子靶向药物,目前已经有4个聚腺苷二磷酸核糖聚合酶抑制剂批准上市,在治疗乳腺癌以及卵巢癌患者过程中取得较大效果。本文将综述聚腺苷二磷酸核糖聚合酶抑制剂的主要功能和作用机制等,了解聚腺苷二磷酸核糖聚合酶抑制剂在BRCA胚系突变乳腺癌治疗中的具体作用。     

Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress

Poly (ADP-ribose) polymerase is a zinc-finger DNA-binding enzyme which detects and signals DNA strand breaks generated either directly during base excision repair, or indirectly by genotoxic agents such as oxygen radicals. In response to genotoxic injury, PARP catalyses the synthesis of poly (ADP-ribose), from its substrate beta-NAD+ and this polymer is covalently attached to several nuclear proteins and PARP itself. As a result, PARP converts DNA breaks into intracellular signals which activate DNA repair programs or cell death options. Several studies have also shown that PARP is involved in either necrosis and subsequent inflammation or apoptosis. Although this enzyme is not indispensable during the latter cell death program, it has been demonstrated that PARP plays a facilitating role in this process. PARP is activated at an intermediate stage of apoptosis and is then cleaved and inactivated at a late stage by apoptotic proteases, namely caspase-3/CPP-32/Yama/apopain and caspase-7. This cleavage prevents necrosis during apoptosis, avoiding inflammation. All these functions, and the observation that PARP is an abundant and highly conserved enzyme, suggest that this enzyme plays a pivotal role, particularly in the maintenance of genomic DNA stability, apoptosis and in the response to oxidative stress. Since these situations are found in cancer, inflammation, autoimmunity (such as diabetes), myocardial dysfunction, certain infections, ageing and radiation/chemical exposure, attempts have been made to modulate PARP activity. With regard to the increasing interest towards PARP, the aim of this review is to explain the cellular role of PARP and the advantages of modulating its activity in diverse preventive or therapeutic strategies.     

聚腺苷二磷酸核糖聚合酶抑制剂在神经保护方面的研究进展

作者对聚腺苷二磷酸核糖聚合酶[poly（ADP—ribose）polymerase，PARP]的结构亚型和生物学功能做了简要介绍。归纳了近几年PARP抑制剂在神经保护方面的研究成果。并从结构分类的角度探讨了部分具有应用前景的化合物的构效关系。     

Poly (ADP-ribose) polymerase, nitric oxide and cell death.

Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. Excessive activation of PARP, however, can deplete tissue stores of nicotinamide adenine dinucleotide (NAD), the PARP substrate which, with the resultant depletion of ATP, leads to cell death. In many cases of CNS damage, for example vascular stroke, nitric oxide release is a key stimulus to DNA damage and PARP activation. In conditions as diverse as focal cerebral ischaemia, myocardial infarction and toxin-induced diabetes, PARP inhibitors and PARP gene deletion afford dramatic protection from tissue damage. Accordingly, PARP inhibitors could provide novel therapeutic approaches in a wide range of clinical disorders.     

The emerging role of poly(ADP-Ribose) polymerase inhibitors in cancer treatment

Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors have been shown to sensitize tumors to DNA-damaging agents and to also selectively kill homologous recombination repair-defective cancers, such as those arising in BRCA1 and BRCA2 mutation carriers. Recent proof-of-concept clinical studies have demonstrated the safety and substantial antitumor activity of the PARP inhibitor, olaparib in BRCA1/2 mutation carriers, highlighting the wide therapeutic window that can be achieved with this synthetic lethal strategy. Likewise, the PARP inhibitor, BSI-201, in combination with carboplatin and gemcitabine have produced promising results in "triple-negative" breast cancers. There are also currently numerous other PARP inhibitors in clinical development. The potential broader therapeutic application of these approaches to a wide range of sporadic tumors harboring specific defects in the homologous recombination repair pathway has generated a great deal of excitement within the oncology community. This review discusses the rationale for targeting PARP and details the strategies and challenges involved in the clinical development of such inhibitors and their future potential applications in cancer medicine.     

Potential clinical applications of poly(ADP-ribose) polymerase (PARP) inhibitors.

Poly(ADP-ribose) polymerases (PARPs) are defined as cell signaling enzymes that catalyze the transfer of ADP-ribose units from NAD(+)to a number of acceptor proteins. PARP-1, the best characterized member of the PARP family, that presently includes six members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress (oxygen radicals, ionizing radiations and monofunctional alkylating agents). Due to its involvement either in DNA repair or in cell death, PARP-1 is regarded as a double-edged regulator of cellular functions. In fact, when the DNA damage is moderate, PARP-1 participates in the DNA repair process. Conversely, in the case of massive DNA injury, elevated PARP-1 activation leads to rapid NAD(+)/ATP consumption and cell death by necrosis. Excessive PARP-1 activity has been implicated in the pathogenesis of numerous clinical conditions such as stroke, myocardial infarction, shock, diabetes and neurodegenerative disorders. PARP-1 could therefore be considered as a potential target for the development of pharmacological strategies to enhance the antitumor efficacy of radio- and chemotherapy or to treat a number of clinical conditions characterized by oxidative or NO-induced stress and consequent PARP-1 activation. Moreover, the discovery of novel functions for the multiple members of the PARP family might lead in the future to additional clinical indications for PARP inhibitors.     

Poly(ADP-ribose) polymerase inhibitors in the prevention of neuronal cell death

Poly(ADP-ribose) polymerase is a nucleic enzyme that promotes energy-dependent repair of DNA, thus helping to protect against DNA fragmentation. Overactivation of PARP, for example in the context of apoptosis, may contribute to neuronal cell death. This article briefly reviews claims for PARP inhibitors as agents for the prevention of neuronal cell death, registered in the period 1998 – December 2001. Biological data are sparse in these patents, few claims are backed by in vitro biochemical data and fewer still with in vivo animal model data. The latter have used animal models of ischaemia rather than of neurodegeneration. The place of PARP inhibitors as a clinical therapy to prevent neuronal cell death remains to be determined.