The Institute of Cancer Research, London, United Kingdom.
Int J Radiat Oncol Biol Phys. 2013 Mar 15;85(4):1110-8. doi: 10.1016/j.ijrobp.2012.08.006. Epub 2012 Sep 14.
To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation.
Colony and mechanistic in vitro assays and a xenograft in vivo model.
SAR-020106 suppressed-radiation-induced G2/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G1 arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model.
The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.
探讨强效 Chk1 抑制剂（SAR-020106）与放疗联合的活性。
集落和机制的体外检测和异种移植的体内模型。
SAR-020106 抑制了辐射诱导的 G2/M 期阻滞，并仅在 p53 缺陷型肿瘤细胞中降低了集落存活能力。SAR-020106 促进了所有细胞系照射后的有丝分裂进入，但 p53 缺陷型细胞可能会发生凋亡或成为非整倍体，而 p53 野生型细胞则经历了有丝分裂后的 G1 期阻滞，随后是正常的细胞周期再进入。联合使用 SAR-020106 和放疗后，所有细胞系中同源重组介导的 DNA 损伤修复均受到抑制。只有在 p53 缺陷型细胞系中观察到 pan-γH2AX 染色的凋亡细胞数量显著增加。在临床上相关的人头颈癌细胞异种移植模型中，体内疗效得到了证实。
Chk1 抑制剂 SAR-020106 是 p53 信号缺陷的肿瘤细胞系中的一种有效的放射增敏剂。
