Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
Semin Radiat Oncol. 2010 Oct;20(4):274-81. doi: 10.1016/j.semradonc.2010.06.001.
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 (PTEN) 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.
DNA 双链断裂（DSBs）在临床放射治疗过程中诱导，是细胞死亡的有力诱导剂。聚（ADP-核糖）聚合酶（PARP）-1 是一种 113kD 的核蛋白，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，已经开发出了强效和特异性的 PARP 活性抑制剂，它们在体外和体内都是有效的肿瘤细胞放射增敏剂。由于合成致死性，PARP 抑制剂可能作为单一药物在具有 DNA 损伤和修复基因（如 ATM、BRCA1、BRCA2 和 NBS1）或参与磷酸酶和张力蛋白同系物基因（PTEN）信号的基因缺陷的患者中具有高度疗效（如 ATM、BRCA1、BRCA2 和 NBS1）或参与磷酸酶和张力蛋白同系物基因（PTEN）信号的基因缺陷。特定 DNA 修复途径的缺陷似乎也增强了 PARP 抑制的放射增敏作用。除了固有遗传学之外，肿瘤细胞还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、靶向内皮细胞和肿瘤血管系统，以及修复缺陷性缺氧细胞内对 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，因此仔细安排这些药物与放射治疗联合使用可能会维持治疗比率并增加肿瘤的放射治愈率。
