Milas Luka, Fan Zhen, Andratschke Nicolaus H, Ang K Kian
Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):966-71. doi: 10.1016/j.ijrobp.2003.08.035.
Evidence is rapidly mounting that dysregulated epidermal growth factor receptor (EGFR) signaling is one of the underlying mechanisms of more aggressive tumor behavior and increased tumor resistance to cytotoxic agents, including radiotherapy (RT). This has led to extensive preclinical and clinical studies aimed at developing effective treatment strategies that counteract EGFR-mediated signaling. In this article, we review preclinical studies, primarily from our laboratory, addressing the role of EGFR in tumor radioresponse and the use of C225, a human-mouse chimeric anti-EGFR monoclonal antibody, to improve the results of RT.
Mouse carcinomas were used to study the influence of EGFR on tumor radioresponse. EGFR expression was assessed by Western blot analysis, and cDNA transfection experiments were performed to determine a causal relationship between EGFR and tumor cell radioresistance. A431 human tumor xenografts growing in nude mice were used to test whether blockade of EGFR with C225 anti-EGFR antibody enhances tumor radioresponse.
Our studies showed that high levels of EGFR were associated with decreased tumor radiocurability of murine carcinomas. The causal role of EGFR in mediating cellular resistance to RT was demonstrated by transfecting the EGFR cDNA into the cells with low levels of EGFR. The EGFR-high expression-transfected clones became more resistant to RT. RT activated EGFR and its downstream signaling pathways in radioresistant, but not in radiosensitive, tumors, which can be regarded as an adaptive response to radiation damage. Additional studies investigated whether blockade of EGFR and inhibition of EGFR-mediated downstream signaling can be exploited for therapeutic purposes. The results described here showed that treatment of human tumor xenografts with C225 can markedly enhance the tumor response to RT, as assessed by both tumor growth delay and the tumor cure rate.
The findings from our in vivo preclinical studies suggest that overexpression of EGFR could serve as a predictor of tumor treatment outcome by RT and as a therapeutic target to enhance the efficacy of RT. This therapeutic strategy is currently being explored in patients with head-and-neck cancers.
越来越多的证据表明，表皮生长因子受体（EGFR）信号失调是肿瘤行为更具侵袭性以及肿瘤对包括放射治疗（RT）在内的细胞毒性药物耐药性增加的潜在机制之一。这促使人们开展了广泛的临床前和临床研究，旨在开发有效的治疗策略来对抗EGFR介导的信号传导。在本文中，我们回顾了主要来自我们实验室的临床前研究，探讨了EGFR在肿瘤放射反应中的作用以及使用人鼠嵌合抗EGFR单克隆抗体C225来改善放疗效果。
使用小鼠癌模型来研究EGFR对肿瘤放射反应的影响。通过蛋白质印迹分析评估EGFR表达，并进行cDNA转染实验以确定EGFR与肿瘤细胞放射抗性之间的因果关系。使用在裸鼠体内生长的A431人肿瘤异种移植模型来测试用C225抗EGFR抗体阻断EGFR是否能增强肿瘤放射反应。
我们的研究表明，高水平的EGFR与小鼠癌的肿瘤放射可治愈性降低相关。通过将EGFR cDNA转染到低水平EGFR的细胞中，证明了EGFR在介导细胞对放疗的抗性中的因果作用。EGFR高表达转染的克隆对放疗更具抗性。放疗激活了抗辐射肿瘤而非辐射敏感肿瘤中的EGFR及其下游信号通路，这可被视为对辐射损伤的一种适应性反应。进一步的研究探讨了阻断EGFR和抑制EGFR介导的下游信号传导是否可用于治疗目的。此处描述的结果表明，用C225治疗人肿瘤异种移植模型可显著增强肿瘤对放疗的反应，这通过肿瘤生长延迟和肿瘤治愈率来评估。
我们体内临床前研究的结果表明，EGFR的过表达可作为RT治疗肿瘤结果的预测指标，并作为增强RT疗效的治疗靶点。目前正在对头颈部癌患者探索这种治疗策略。
