Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft.
Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft.
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DOI：
10.1158/1535-7163.mct-11-0278
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发表时间：
2011-10
影响因子：
5.7
通讯作者：
Stratford IJ
中科院分区：
文献类型：
--
作者：
Senra JM;Telfer BA;Cherry KE;McCrudden CM;Hirst DG;O'Connor MJ;Wedge SR;Stratford IJ
聚ADP核糖聚合酶-1是DNA链断裂修复的关键酶。PARP-1的抑制增加了辐射杀死肿瘤细胞的有效性。然而，尽管这些体外放射增敏作用的机制已被充分理解，但体内潜在机制尚不清楚。烟酰胺是一种结构上与第一代PARP-1抑制剂3-氨基苯甲酰胺相关的药物，通过防止肿瘤血流短暂停止来减少肿瘤缺氧，从而改善肿瘤氧合和对放疗的敏感性。在这里，我们研究奥拉帕尼，一种有效的PARP-1抑制剂，是否不仅通过抑制DNA修复，而且通过改变非小细胞肺癌的肿瘤血管血流动力学来增强放射治疗。在辐照的Calu-6和A549细胞中，奥拉帕尼增强了辐射的细胞毒性效应（SER 10 =1.5和1.3），处理后DNA双链断裂持续至少24小时。Calu-6异种移植物与奥拉帕尼和分次放疗的联合治疗相对于单独放疗引起显著的肿瘤消退（p=0.007）。为了确定这种放射增敏是否仅仅是由于对DNA修复的影响，我们使用背侧窗室模型来建立药物/放射对血管动力学的影响。奥拉帕尼单独给药，单次或多次每日给药，或与分次放疗联合给药，增加了肿瘤血管的灌注。此外，在苯妥英钠预收缩动脉中的离体测定证实奥拉帕尼具有比烟酰胺更高的血管舒张特性。这项研究表明，奥拉帕尼值得考虑在临床肿瘤学环境（如NSCLC）中与放疗联合进行进一步开发。
Poly(ADP-ribose) polymerase-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, while the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3-aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular haemodynamics in non-small cell lung carcinoma. In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (SER10=1.5 and 1.3) and DNA double strand breaks persisted for at least 24 h after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (p=0.007) relative to radiotherapy alone. To determine whether this radiosensitisation was due solely to effects on DNA repair we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine pre-constricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC.