Department of Oral and Maxillofacial Plastic Surgery (Head: Alexander C. Kübler), University Hospital Würzburg, Pleicherwall 2, 97070 Würzburg, Germany.
J Craniomaxillofac Surg. 2013 Oct;41(7):623-9. doi: 10.1016/j.jcms.2012.12.006. Epub 2013 Jan 31.
Over-expression of epidermal growth factor receptor (EGFR) has been observed in a variety of epithelial tumours. The selective inhibition of the associated signalling pathway using monoclonal antibodies appears to be a promising therapeutic target. Individual differences in response rates, particularly against highly selective chemotherapeutic agents, underline the need for further research of the molecular basis of this process. Previously described resistance mechanisms are not able to explain all refractory responses. Several subgroups of the melanoma-associated antigens (MAGE) tumour antigens were described in connection with regulatory functions relating to the cell cycle and chemosensitivity.
In the present study, five cell lines of human squamous cell carcinomas were treated with cetuximab and panitumumab (0.01-100 μg/ml) over a period of 24 or 48 h. The efficacy of the agents used was measured dynamically using real-time cell analysis (RTCA). Subsequently, the expression levels of MAGE-A1, -A5, -A8, -A9, -A11 and -A12 were determined by RT-qPCR. A correlation between chemosensitivity and MAGE-A expression was investigated.
The tumour cell lines exhibited a very low overall response to the chemotherapy drugs. Only one cell line showed a cytostatic effect after treatment with cetuximab and panitumumab. This effect, however, was significant only for panitumumab. The expression of MAGE-A12 was significantly associated with greater efficacy of panitumumab. The expression of MAGE-A5 and -A8 was associated with poorer response rates after panitumumab treatment. Due to an insignificant effect of cetuximab on the number of viable cells, no correlation with the MAGE-A levels was observed.
For the first time, these results show a correlation between the efficacies of EGFR inhibitors and various MAGE-A subgroups in the treatment of HNSCC. Determining the MAGE-A status could help to improve the success of anti-tumour drug therapy. In addition, evaluating MAGE-A levels might be an important tool in the development of patient-specific treatment protocols.
表皮生长因子受体 (EGFR) 的过度表达已在多种上皮肿瘤中观察到。使用单克隆抗体选择性抑制相关信号通路似乎是一种有前途的治疗靶点。反应率的个体差异，特别是针对高度选择性的化疗药物，突显了进一步研究该过程分子基础的必要性。以前描述的耐药机制无法解释所有的耐药反应。黑色素瘤相关抗原 (MAGE) 肿瘤抗原的几个亚组与与细胞周期和化疗敏感性相关的调节功能有关。
在本研究中，用人鳞状细胞癌细胞系，用西妥昔单抗和帕尼单抗（0.01-100μg/ml）处理 24 或 48 小时。使用实时细胞分析（RTCA）动态测量所用药物的功效。随后，通过 RT-qPCR 确定 MAGE-A1、-A5、-A8、-A9、-A11 和 -A12 的表达水平。研究了化疗敏感性与 MAGE-A 表达之间的相关性。
肿瘤细胞系对化疗药物的总体反应非常低。只有一个细胞系在用西妥昔单抗和帕尼单抗处理后显示出细胞生长抑制作用。然而，这种作用仅在帕尼单抗中是显著的。MAGE-A12 的表达与帕尼单抗的疗效显著相关。MAGE-A5 和 -A8 的表达与帕尼单抗治疗后的反应率较差相关。由于西妥昔单抗对活细胞数量的影响不大，因此未观察到与 MAGE-A 水平的相关性。
这些结果首次表明，在治疗头颈部鳞状细胞癌中，EGFR 抑制剂的疗效与各种 MAGE-A 亚群之间存在相关性。确定 MAGE-A 状态有助于提高抗肿瘤药物治疗的成功率。此外，评估 MAGE-A 水平可能是制定患者特异性治疗方案的重要工具。
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