Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model
Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model
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DOI：
10.1158/1078-0432.ccr-04-2102
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发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Shin, DM
中科院分区：
文献类型：
--
作者：
Zhang, X;Chen, ZG;Shin, DM
目的：我们的前期研究表明，同时靶向表皮生长因子受体（EGFR）酪氨酸激酶和环氧合酶-2（考克斯-2）在体外可相加或协同抑制头颈部鳞状细胞癌（SCCHN）的生长。实验设计：在注射人SCCHN细胞系Tu 212之前，用对照（1%吐温80）、单独的ZD 1839（50 mg/kg）、单独的塞来昔布（50 mg/kg）或相同剂量的ZD 1839和塞来昔布的组合预处理裸鼠7天。结果：与对照组（P < 0.001）、ZD 1839组（P = 0.005）和塞来昔布组（P < 0.001）相比，联合用药组肿瘤生长明显受到抑制。同时，与所有其他三组相比，在联合治疗中观察到肿瘤进展的显著延迟。分子分析表明，联合治疗显着降低前列腺素E代谢产物的产生。这两种药物联合使用的协同作用也与磷酸化EGFR、磷酸化细胞外信号调节激酶、磷酸化信号转导和转录激活因子3水平的下调以及血管内皮生长因子和Ki-67表达的降低相关。具体而言，EGFR和考克斯-2的基因沉默的小干扰RNA进一步证实了合作antitumor effects.Conclusion：目前的结果强烈表明，联合治疗对肿瘤进展的协同作用是通过阻断EGFR和考克斯-2相关通路介导的。这种联合方案可能为SCCHN的癌症治疗和化学预防提供了一种有希望的策略。
Purpose: Our previous study revealed that simultaneously targeting epidermal growth factor receptor (EGFR) tyrosine kinase and cyclooxygenase-2 (COX-2) additively or synergistically inhibited growth of squamous cell carcinoma of the head and neck (SCCHN) in vitro. However, an in vivo efficacy of this combined treatment in SCCHN has not been studied.Experimental Design: Nude mice were pretreated with control (1% Tween 80), ZD1839 (50 mg/kg) alone, celecoxib (50 mg/kg) alone, or a combination of ZD1839 and celecoxib at the same dosages for 7 days before injection of a human SCCHN cell line Tu212. The animals were continuously treated with the agents 5 days a week for about 11 weeks.Results: Tumor growth in the combined treatment was significantly inhibited compared with the control (P < 0.001), ZD1839 (P = 0.005), or celecoxib (P < 0.001). At the same time, a dramatic delay of tumor progression was observed in the combined treatment compared with all other three groups. Molecular analysis showed that the combined treatment significantly decreased prostaglandin E metabolite production. The cooperative effect of these two agents in combination was also associated with down-regulation of phosphorylated EGFR, phosphorylated extracellular signal-regulated kinase, and phosphorylated signal transducers and activators of transcription 3 levels and reduction of vascular endothelial growth factor and Ki-67 expression. Specifically, gene silencing of both EGFR and COX-2 by small interfering RNA further confirmed the cooperative antitumor effect.Conclusion: The current results strongly suggest that a cooperative effect of the combined treatment on tumor progression is mediated through blocking both EGFR- and COX-2-related pathways. This combination regimen may provide a promising strategy for cancer therapy and chemoprevention in SCCHN.