a Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Radiat Res. 2013 Oct;180(4):414-21. doi: 10.1667/RR3349.2. Epub 2013 Sep 23.
Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model.
表皮生长因子受体 (EGFR) 抑制药物西妥昔单抗可提高头颈部鳞状细胞癌 (HNSCC) 患者放射治疗的疗效，但仅在部分患者中有效。因此，为了改善患者选择，需要更好地了解影响治疗效果的肿瘤特征。在此，我们研究了西妥昔单抗对 HNSCC 异种移植模型中放射诱导的 DNA 损伤修复的影响，该模型显示西妥昔单抗与放射治疗具有协同作用（SCCNij185），以及一种 HNSCC 模型，该模型显示西妥昔单抗与放射治疗无相加作用（SCCNij153）。在这两种肿瘤模型中，照射后均可见 53BP1 和 Rad51 焦点数量明显增加。低氧和常氧肿瘤区域的 53BP1 焦点水平相当，但 Rad51 焦点数量在常氧区域明显高于低氧区域（P <0.05）。在 SCCNij185 和 SCCNij153 异种移植瘤中，与单独放疗相比，西妥昔单抗联合放疗组肿瘤中 53BP1 焦点数量增加。在 SCCNij185 中，这一增加在常氧肿瘤区域具有统计学意义（P = 0.04），而在 SCCNij153 中，低氧和常氧区域均有统计学意义（P = 0.007 和 P = 0.02）。与单独放疗相比，西妥昔单抗联合放疗时 Rad51 焦点数量无显著差异。在 SCCNij185 中，当西妥昔单抗联合放疗时，pEGFR 和 pERK1/2 水平降低，但在 SCCNij153 中则不然。在西妥昔单抗和放疗治疗 4 天后，SCCNij185 肿瘤中的细胞凋亡也仅增加（P <0.01）。综上所述，西妥昔单抗抑制了两种 HNSCC 模型中的 DNA 修复，但这种作用并不能预测西妥昔单抗在体内的放射增敏作用。这种缺乏相关性可能与西妥昔单抗和放疗对 ERK1/2 信号的不同作用以及在耐药模型中西妥昔单抗和放疗诱导的细胞凋亡减少有关。
