Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma
Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma
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DOI：
10.1158/1078-0432.ccr-08-2407
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Hoeller, Christoph
中科院分区：
文献类型：
--
作者：
Schicher, Nikolaus;Paulitschke, Verena;Hoeller, Christoph
目的：黑色素瘤是最具侵袭性的癌症之一，一旦扩散到远处，目前没有治愈的机会。晚期III和IV期的治疗选择非常有限，主要是姑息治疗，仅有20%的病例显示出类似的反应。本研究旨在探讨表皮生长因子受体抑制剂厄洛替尼和血管内皮生长因子单抗贝伐单抗联合应用对黑色素瘤的影响。实验设计与结果：所有受试细胞株均表达表皮生长因子受体，厄洛替尼可抑制MEK/细胞外信号调节激酶和AKT信号通路的激活。然而，在体外，厄洛替尼或贝伐单抗对肿瘤细胞的增殖没有影响，在三维Matrigel试验中观察到厄洛替尼治疗的侵袭潜力降低。此外，这两种药物都抑制内皮细胞的增殖和发芽。在体内，在严重联合免疫缺陷小鼠异种移植模型中，厄洛替尼和贝伐单抗联合治疗的肿瘤体积缩小优于两种药物单独使用时的相加作用。与对照组或单一治疗组相比，这与细胞增殖减少、细胞凋亡增加和肿瘤血管生成减少有关。结论：目前的数据有力地支持了厄洛替尼和贝伐单抗作为转移性黑色素瘤的一种新的治疗方案的使用。
Purpose: Melanoma is one of the most aggressive types of cancer with currently no chance of cure once the disease has spread to distant sites. Therapeutic options for advanced stage III and IV are very limited, mainly palliative, and show response in only similar to 20% of all cases. The presented preclinical study was done to investigate the influence of a combined treatment of the epidermal growth factor receptor inhibitor erlotinib and the vascular endothelial growth factor monoclonal antibody bevacizumab in melanoma.Experimental Design and Results: The epidermal growth factor receptor was expressed in all cell lines tested, and treatment with erlotinib did inhibit the activation of the MEK/extracellular signal-regulated kinase and AKT signaling pathways. Whereas in vitro no influence on tumor cell proliferation was seen with erlotinib or bevacizumab monotherapy, a decreased invasive potential on erlotinib treatment in a three-dimensional Matrigel assay was observed. Furthermore, both drugs inhibited proliferation and sprouting of endothelial cells. In vivo, in a severe combined immunodeficient mouse xenotransplantation model, reduction in tumor volume under combined treatment with erlotinib and bevacizumab was superior to the additive effect of both single agents. This was associated with reduced cell proliferation, increased apoptosis, and a reduction in tumor angiogenesis compared with control or single treatment groups. Likewise, the reduction in the extent of lymph node and lung metastasis was most pronounced in animals treated with both drugs.Conclusion: The presented data strongly support the use of a combination of erlotinib and bevacizumab as a novel treatment regimen for metastatic melanoma.