Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression.
Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression.
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DOI：
10.1007/s00280-014-2610-x
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发表时间：
2014-12
影响因子：
3
通讯作者：
Nakanishi, Yoichi
中科院分区：
文献类型：
--
作者：
Li, Heyan;Takayama, Koichi;Wang, Shuo;Shiraishi, Yoshimasa;Gotanda, Keisuke;Harada, Taishi;Furuyama, Kazuto;Iwama, Eiji;Ieiri, Ichiro;Okamoto, Isamu;Nakanishi, Yoichi
埃洛替尼是一种表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)，贝伐单抗是一种抗血管内皮生长因子(VEGF)药物，是治疗晚期非小细胞肺癌(NSCLC)的有前途的药物。我们的研究旨在确定是否存在加入贝伐单抗在体内外增强厄洛替尼对NSCLC肿瘤的抗肿瘤活性的条件。MTS用于非小细胞肺癌细胞(PC9、11-18、H1975、H157、H460和A549)的体外生长实验。采用ELISA法检测细胞和肿瘤组织中的血管内皮生长因子蛋白。建立对厄洛替尼具有原发耐药性的H157、H460和A549小鼠异种移植模型，分别用厄洛替尼和贝伐单抗或单独用药治疗。用高效液相色谱法测定肿瘤组织中厄洛替尼的浓度。贝伐单抗在体外不能抑制NSCLC细胞的生长。在对厄洛替尼耐药的NSCLC细胞中，H157细胞的VEGF蛋白表达水平最高，其次是H460和A549细胞。在体内，贝伐单抗仅在高水平(H157)和/或中等水平(H460)的异种移植模型中显著抑制肿瘤生长。联合应用厄洛替尼和贝伐单抗可部分逆转H157移植瘤对厄洛替尼的耐药性(高水平的血管内皮生长因子)，但不能逆转H460(中度)或A549(低水平)移植瘤对厄洛替尼的耐药性。这些结果支持联合抗血管内皮生长因子治疗可以增强抗EGFR治疗的抗肿瘤活性和/或部分逆转对EGFR TKI的耐药性，这可能是通过增加高表达VEGF蛋白的特定肿瘤中EGFR TKI的浓度来实现的。本文的在线版本(doi：10.1007/s00280-0142610-x)包含补充材料，可供授权用户使用。
Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo. MTS was for NSCLC cell (PC9, 11–18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography. Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts. These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein. The online version of this article (doi:10.1007/s00280-014-2610-x) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Choi YL;Sun JM;Cho J;Rampal S;Han J;Parasuraman B;Guallar E;Lee G;Lee J;Shim YM
通讯作者：
Shim YM
影响因子：
5.8
作者：
Cohen, Martin H.;Gootenberg, Joe;Pazdur, Richard
通讯作者：
Pazdur, Richard
影响因子：
11.5
作者：
Schicher, Nikolaus;Paulitschke, Verena;Hoeller, Christoph
通讯作者：
Hoeller, Christoph
影响因子：
8.8
作者：
Shaheen RM;Ahmad SA;Liu W;Reinmuth N;Jung YD;Tseng WW;Drazan KE;Bucana CD;Hicklin DJ;Ellis LM
通讯作者：
Ellis LM
DOI：
10.1016/s0140-6736(11)60545-x
发表时间：
2011-05-28
期刊：
Lancet (London, England)
影响因子：
--
作者：
Herbst RS;Ansari R;Bustin F;Flynn P;Hart L;Otterson GA;Vlahovic G;Soh CH;O'Connor P;Hainsworth J
通讯作者：
Hainsworth J