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首页> 外文期刊>Radiotherapy and oncology: Journal of the European Society for Therapeutic Radiology and Oncology >A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia.
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A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia.

机译：一种新型的聚（ADP-核糖）聚合酶抑制剂ABT-888，在缺氧条件下对人类恶性肿瘤细胞放射增敏。

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The chemo- and radioresponse of tumor cells can be determined by genetic factors (e.g., those that modify cell cycle arrest, DNA damage repair or cell death) and microenvironmental factors, such as hypoxia. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that rapidly recognizes and binds to DNA breaks to facilitate DNA strand break repair. Pre-clinical data suggest that PARP inhibitors (PARPi) may potentiate the effects of radiotherapy and chemotherapy. However, it is unclear as to whether PARPi are effective against hypoxic cells. We therefore tested the role for a novel PARPi, ABT-888, as a radiosensitizing agent under hypoxic conditions. Using human prostate (DU-145, 22RV1) and non-small cell lung (H1299) cancer cell lines, we observed that ABT-888 inhibited both recombinant PARP activity and intracellular PARP activity (86% to 92% decrease in all 3 cells lines following 2.5muM treatment). ABT-888 was toxic to both oxic and hypoxic cells. When ABT-888 was combined with ionizing radiation (IR), clonogenic radiation survival was decreased by 40-50% under oxic conditions. Under acute hypoxia, ABT-888 radiosensitized malignant cells to a level similar to oxic radiosensitivity. To our knowledge, this is the first study to demonstrate that inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of IR-PARPi has the potential to improve the therapeutic ratio of radiotherapy.
机译：肿瘤细胞的化学和放射反应可以通过遗传因素（例如改变细胞周期停滞，DNA损伤修复或细胞死亡的因素）和微环境因素（例如缺氧）来确定。聚（ADP-核糖）聚合酶（PARP）是一种核酶，可以快速识别并结合DNA断裂，从而促进DNA链断裂的修复。临床前数据表明，PARP抑制剂（PARPi）可能会增强放疗和化疗的作用。但是，尚不清楚PARPi是否对缺氧细胞有效。因此，我们在缺氧条件下测试了新型PARPi ABT-888作为放射增敏剂的作用。使用人前列腺（DU-145、22RV1）和非小细胞肺癌（H1299）癌细胞系，我们观察到ABT-888抑制了重组PARP活性和细胞内PARP活性（在所有3种细胞系中均降低了86％至92％） 2.5μM处理后）。 ABT-888对有氧和低氧细胞均具有毒性。当ABT-888与电离辐射（IR）结合使用时，在有氧条件下，无源辐射的存活率降低了40-50％。在急性缺氧条件下，ABT-888对恶性细胞的放射敏感性达到与有氧放射敏感性相似的水平。据我们所知，这是第一个证明抑制PARP活性可以使缺氧癌细胞敏感的研究，并且IR-PARPi的组合具有提高放疗治疗率的潜力。

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