Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9187, USA.
Int J Radiat Oncol Biol Phys. 2012 Nov 15;84(4):e507-14. doi: 10.1016/j.ijrobp.2012.05.035. Epub 2012 Jul 12.
Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT.
The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used.
Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G(2)-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7.
This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.
放射治疗（RT）是治疗非小细胞肺癌（NSCLC）的主要方法之一。然而，由于这些肿瘤固有的放射抵抗性，许多患者经历 RT 失败，导致相当大的肿瘤进展，包括区域淋巴结和远处转移。这项临床前研究评估了新一代细胞周期蛋白依赖性激酶（Cdk）抑制剂 AZD5438 作为几种 NSCLC 模型的放射增敏剂的疗效，这些模型对常规分割 RT 具有特异性抗性。
通过存活分数、细胞周期分布、凋亡、DNA 双链断裂（DSB）修复和同源重组（HR）测定，在 3 种 NSCLC 细胞系（A549、H1299 和 H460）中确定电离辐射与 AZD5438（Cdk1、2 和 9 的高度特异性抑制剂）联合作用的体外效果。对于体内研究，使用荷人异种移植肿瘤的裸鼠动物模型。
AZD5438 处理 NSCLC 细胞可显著增强细胞放射敏感性（剂量增强比范围为 1.4 至 1.75）。AZD5438 的放射增敏作用在放射抗性细胞系（A549 和 H1299）中更大。通过抑制 Cdk1、延长 G2-M 期阻滞、抑制 HR、延迟 DNA DSB 修复和增加凋亡，特异性增强放射敏感性。AZD5438 与照射联合治疗还增强了肿瘤生长延迟，增强因子范围为 1.2-1.7。
这项研究支持评估新一代 Cdk 抑制剂，如 AZD5438，作为 NSCLC 模型中的有效放射增敏剂，特别是在表现出不同内在放射反应的肿瘤中。
