Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sci Rep. 2019 Dec 11;9(1):18882. doi: 10.1038/s41598-019-54796-6.
DNA-dependent protein kinase (DNA-PK) has been shown to play a crucial role in repair of DNA double-strand breaks, facilitating nonhomologous end-joining. DNA-PK inhibitors have the potential to block DNA repair and therefore enhance DNA-damaging agents. M3814 is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including radiotherapy and topoisomerase II inhibitors. Here we evaluated the activity of M3814 in combination with multiple topoisomerase II inhibitors, doxorubicin, etoposide, and pegylated liposomal doxorubicin (PLD) in vivo, utilizing ovarian cancer xenografts. Using cell lines representative of P53 wild-type ovarian cancer (A2780), and P53 mutant ovarian cancer (SKOV3), cells were implanted in the flank of athymic nude female mice. Mice were treated with vehicle, M3814 alone, topoisomerase II inhibitor alone, and M3814 in combination with topoisomerase II inhibitor, and change in tumor volume over time was documented. The addition of M3814 was well tolerated. We demonstrated that M3814 shows limited efficacy as a single agent in ovarian cancer models. The combination of M3814 with PLD showed enhanced activity over PLD as a single agent. Further study of this combination is warranted.
DNA 依赖性蛋白激酶（DNA-PK）已被证明在修复 DNA 双链断裂中发挥关键作用，促进非同源末端连接。DNA-PK 抑制剂有可能阻断 DNA 修复，从而增强 DNA 损伤剂的作用。M3814 是一种 DNA-PK 抑制剂，在与包括放射治疗和拓扑异构酶 II 抑制剂在内的 DNA 损伤剂联合应用时具有临床前活性。在这里，我们评估了 M3814 与多种拓扑异构酶 II 抑制剂（阿霉素、依托泊苷和聚乙二醇化脂质体阿霉素（PLD））联合在卵巢癌异种移植模型中的体内活性。使用代表 P53 野生型卵巢癌（A2780）和 P53 突变型卵巢癌（SKOV3）的细胞系，将细胞植入裸鼠的侧腹。将小鼠用载体、M3814 单独、拓扑异构酶 II 抑制剂单独以及 M3814 与拓扑异构酶 II 抑制剂联合处理，并记录随时间推移肿瘤体积的变化。添加 M3814 的耐受性良好。我们证明 M3814 作为单一药物在卵巢癌模型中疗效有限。M3814 与 PLD 的联合应用显示出比 PLD 作为单一药物更强的活性。需要进一步研究这种联合应用。
