Poly(ADP-Ribose) Polymerase Inhibition as a Model for Synthetic Lethality in Developing Radiation Oncology Targets
Poly(ADP-Ribose) Polymerase Inhibition as a Model for Synthetic Lethality in Developing Radiation Oncology Targets
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DOI：
10.1016/j.semradonc.2010.06.001
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发表时间：
2010-10-01
影响因子：
3.5
通讯作者：
Bristow, Robert G.
中科院分区：
文献类型：
--
作者：
Chalmers, Anthony J.;Lakshman, Mina;Bristow, Robert G.
在临床放射治疗过程中诱导的DNA双链断裂（DSB）是细胞死亡的有效诱导剂。多聚ADP核糖聚合酶（Poly（ADP-ribose）polymerase，PARP）-1是一种分子量为113 kD的核蛋白，它能与单链和双链DNA断裂结合，并积极参与DNA单链断裂修复和碱基切除修复。最近，已经开发了PARP活性的有效和特异性化学抑制剂，其是体外和体内有效的肿瘤细胞放射增敏剂。由于具有合成致死性，PARP抑制剂作为单药在肿瘤存在DNA损伤和修复基因（例如ATM、BRCA 1、BRCA 2和NBS 1）的胚系或体细胞缺陷或参与磷酸酶和张力蛋白同源基因（KEN）信号传导的基因缺陷的患者中可能非常有效。特异性DNA修复途径的缺陷似乎也增强了PARP抑制的放射增敏作用。除了固有的遗传学，肿瘤细胞也可能通过多种机制优先对放射治疗敏感，包括增殖依赖性放射增敏、靶向内皮和肿瘤血管系统以及修复缺陷缺氧细胞内对PARP抑制剂的敏感性增加。由于PARP抑制剂的生物活性剂量在I期至II期临床试验中引起的毒性最小，因此这些药物与放射治疗联合使用的仔细安排可能会维持治疗比并增加肿瘤的放射可治愈性。Semin Radiat Oncol 20：274-281 Crown版权所有（C）2010由Elsevier Inc.出版。All rights reserved.
DNA double-strand breaks (DSBs) induced during clinical radiotherapy are potent inducers of cell death. Poly(ADP-ribose) polymerase (PARP)-1 is a 113-kD nuclear protein that binds to both single- and double-strand DNA breaks and is actively involved in DNA single-strand break repair and base excision repair. Recently, potent and specific chemical inhibitors of PARP activity have been developed that are effective tumor cell radiosensitizers in vitro and in vivo. Because of synthetic lethality, PARP inhibitors may be highly effective as a single agent in patients whose tumors have germline or somatic defects in DNA damage and repair genes (eg, ATM, BRCA1, BRCA2, and NBS1) or defects in genes involved in phosphatase and tensin homolog gene (KEN) signaling. Defects in specific DNA repair pathways also appear to enhance the radiosensitizing effects of PARP inhibition. In addition to inherent genetics, tumor cells may also be preferentially sensitized to radiotherapy by diverse mechanisms, including proliferation-dependent radiosensitization, targeting of the endothelium and tumor vasculature, and increased sensitivity to PARP inhibitors within repair-deficient hypoxic cells. Because biologically active doses of PARP inhibitors caused minimal toxicity in phase I to II clinical trials, careful scheduling of these agents in combination with radiotherapy may maintain the therapeutic ratio and increase tumor radiocurability. Semin Radiat Oncol 20:274-281 Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved.