PDF(Pubmed)
Abstract：
Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46-72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.
摘要：
基于顺铂的化学放射疗法（CRT）是晚期宫颈癌（CC）的标准治疗方法，但反应率低（46-72％），顺铂具有肾毒性。因此,迫切需要更好的治疗CC。我们直接比较了,第一次,四种DDR抑制剂(rucaparib/PARPi，VE-821/ATRi,PF-477736/CHK1i和MK-1775/WEE1i)作为单一药剂，并在一组CC细胞中与顺铂和放射疗法（RT）组合。所有抑制剂单独引起浓度依赖性细胞毒性。低ATM和DNA-PKcs水平与更大的VE-821细胞毒性相关。顺铂诱导的ATR，所有细胞系中的CHK1和WEE1活性。顺铂仅激活S期细胞中的PARP，但RT在整个人群中激活了PARP。Rucaparib是最有效的放射增敏剂，VE-821是最有效的化学增敏剂。VE-821，PF-47736和MK-1775减弱了顺铂诱导的S期停滞，但倾向于增加G2期积累。在老鼠身上,顺铂诱导的急性肾损伤与氧化应激和PARP激活相关,并可通过rucaparib预防.因此,虽然所有研究的抑制剂都可能增加CRT的疗效，rucaparib的最大临床潜力可能是限制肾脏损害，这是剂量限制。
