Therapeutic applications of PARP inhibitors: anticancer therapy and beyond.
Therapeutic applications of PARP inhibitors: anticancer therapy and beyond.
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DOI：
10.1016/j.mam.2013.01.006
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发表时间：
2013-12
影响因子：
10.6
通讯作者：
Szabo, Csaba
中科院分区：
文献类型：
--
作者：
Curtin, Nicola J.;Szabo, Csaba
关键词：
本文的目的是描述聚（adp -核糖）聚合酶（PARP）药理学抑制剂治疗各种疾病的现状和潜在的临床翻译。本综述的第一部分总结了PARP抑制剂在各种类型癌症中的临床前和临床数据。在这种情况下，PARP在单链DNA断裂修复中的作用是相关的，如果同源重组（HRR）修复有缺陷，则导致无法修复的复制相关病变，PARP抑制剂在HRR缺陷癌症中的合成致命性。HRR缺陷通常与家族性乳腺癌和卵巢癌相关的BRCA1和2突变有关，但可能有许多其他原因导致HRR缺陷。因此，PARP抑制剂可能是BRCA突变型乳腺癌和卵巢癌的首选药物，如果能够开发出合适的生物标志物来识别HRR缺陷，PARP抑制剂可能会扩展到这些肿瘤之外。多组临床前数据表明，PARP抑制与替莫唑胺、拓扑异构酶抑制剂和电离辐射联合使用可增加细胞毒性和肿瘤生长延迟。单药和联合临床试验正在进行中。本综述第一部分的最后一部分总结了处于临床开发不同阶段的各种PARP抑制剂的现状。本综述的第二部分总结了PARP在选定的非肿瘤适应症中的作用。在许多严重的急性疾病（如中风、神经创伤、循环性休克和急性心肌梗死）中，PARP抑制的临床可翻译性得到了多项临床前数据以及在人体组织样本中显示PARP激活的观察数据的支持。在这些疾病适应症中，氧化应激和硝化应激引起的PARP过度激活会导致细胞坏死和促炎基因表达，从而导致疾病病理。因此，多组临床前数据表明PARP抑制剂在保护活组织和下调炎症反应方面的功效。随着PARP抑制剂在各种癌症中的临床试验的进展，希望能够启动第二轮临床研究，旨在测试PARP抑制剂在各种非肿瘤适应症中的应用。
The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.
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影响因子：
5.7
作者：
Ali M;Kamjoo M;Thomas HD;Kyle S;Pavlovska I;Babur M;Telfer BA;Curtin NJ;Williams KJ
通讯作者：
Williams KJ
影响因子：
6.1
作者：
Benkö, R;Pacher, P;Szabó, C
通讯作者：
Szabó, C
影响因子：
3.6
作者：
Bernges, F;Zeller, WJ
通讯作者：
Zeller, WJ
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.
影响因子：
11.5
作者：
Ali, Majid;Telfer, Brian A.;Williams, Kaye J.
通讯作者：
Williams, Kaye J.