Department of Radiotherapy, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):492-9. doi: 10.1016/j.ijrobp.2011.12.021. Epub 2012 Feb 28.
The use of molecular-targeted agents during radiotherapy of non-small-cell lung cancer (NSCLC) is a promising strategy to inhibit repopulation, thereby improving therapeutic outcome. We assessed the combined effectiveness of inhibiting Aurora B kinase and irradiation on human NSCLC cell lines in vitro.
NSCLC cell lines were exposed to concentrations of AZD1152-hydroxyquinazoline pyrazol anilide (AZD1152-HQPA) inhibiting colony formation by 50% (IC50(clone)) in combination with single dose irradiation or different fractionation schedules using multiple 2-Gy fractions per day up to total doses of 4-40 Gy. The total irradiation dose required to control growth of 50% of the plaque monolayers (TCD50) was determined. Apoptosis, G2/M progression, and polyploidization were also analyzed.
TCD50 values after single dose irradiation were similar for the H460 and H661 cell lines with 11.4 ± 0.2 Gy and 10.7 ± 0.3 Gy, respectively. Fractionated irradiation using 3 × 2 Gy/day, 2 × 2 Gy/day, and 1 × 2 Gy/day schedules significantly increased TCD50 values for both cell lines grown as plaque monolayers with increasing radiation treatment time. This could be explained by a repopulation effect per day that counteracts 75 ± 8% and 27 ± 6% of the effect of a 2-Gy fraction in H460 and H661 cells, respectively. AZD1152-HQPA treatment concomitant to radiotherapy significantly decreased the daily repopulation effect (H460: 28 ± 5%, H661: 10 ± 4% of a 2-Gy fraction per day). Treatment with IC50(clone) AZD1152-HPQA did not induce apoptosis, prolong radiation-induced G2 arrest, or delay cell cycle progression before the spindle check point. However, polyploidization was detected, especially in cell lines without functional p53.
Inhibition of Aurora B kinase with low AZD1152-HQPA concentrations during irradiation of NSCLC cell lines affects repopulation during radiotherapy. Thus, concomitant Aurora B kinase inhibition and irradiation may be a promising strategy for fast repopulating tumors, which are difficult to cure by dose escalation based on conventional fractionation.
在非小细胞肺癌（NSCLC）的放射治疗中使用分子靶向药物是一种有前途的抑制再增殖的策略，从而改善治疗效果。我们评估了抑制 Aurora B 激酶和照射对体外人 NSCLC 细胞系的联合作用。
将 NSCLC 细胞系暴露于浓度为 AZD1152-羟基喹唑啉吡唑苯胺（AZD1152-HQPA），其抑制集落形成的 50%（IC50（克隆）），与单次照射或不同分割方案相结合，每天多次使用 2 Gy 分次，直至总剂量为 4-40 Gy。确定控制 50%斑块单层生长的总照射剂量（TCD50）。还分析了细胞凋亡、G2/M 进展和多倍体化。
单次照射后 TCD50 值在 H460 和 H661 细胞系中分别为 11.4 ± 0.2 Gy 和 10.7 ± 0.3 Gy，相似。使用 3×2 Gy/天、2×2 Gy/天和 1×2 Gy/天的分割照射方案显著增加了作为斑块单层生长的两种细胞系的 TCD50 值，随着放射治疗时间的增加。这可以通过每天的再增殖效应来解释，该效应分别抵消了 H460 和 H661 细胞中 2 Gy 分次的 75±8%和 27±6%的效应。与放疗同时使用 AZD1152-HQPA 治疗可显著降低每日再增殖效应（H460：28±5%，H661：每天 2 Gy 分次的 10±4%）。用 IC50（克隆）AZD1152-HPQA 处理不会诱导细胞凋亡，延长放射诱导的 G2 期阻滞，或在纺锤体检查点之前延迟细胞周期进程。然而，检测到多倍体化，尤其是在没有功能性 p53 的细胞系中。
在 NSCLC 细胞系的照射过程中，用低浓度的 Aurora B 激酶抑制剂 AZD1152-HQPA 抑制 Aurora B 激酶，会影响放疗期间的再增殖。因此，同时抑制 Aurora B 激酶和照射可能是一种很有前途的策略，适用于快速增殖的肿瘤，这些肿瘤难以通过基于常规分割的剂量递增来治愈。
