Urban Hans, Maurer Gabriele D, Luger Anna-Luisa, Lorenz Nadja I, Sauer Benedikt, Stroh Christopher, Trojan Jörg, Mittelbronn Michel, Steinbach Joachim P, Harter Patrick N, Ronellenfitsch Michael W
Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany.
University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany.
Cancers (Basel). 2020 Oct 20;12(10):3050. doi: 10.3390/cancers12103050.
Monoclonal antibodies like cetuximab, targeting the epidermal growth factor receptor (EGFR), and bevacizumab, targeting the vascular endothelial growth factor (VEGF), are an integral part of treatment regimens for metastasized colorectal cancer. However, inhibition of the EGFR has been shown to protect human glioma cells from cell death under hypoxic conditions. In colon carcinoma cells, the consequences of EGFR blockade in hypoxia (e.g., induced by bevacizumab) have not been evaluated yet. LIM1215 and SW948 colon carcinoma and LNT-229 glioblastoma cells were treated with cetuximab, PD153035, and erlotinib and analyzed for cell density and viability. The sequential administration of either cetuximab followed by bevacizumab (CET->BEV) or bevacizumab followed by cetuximab (BEV->CET) was investigated in a LIM1215 (KRAS wildtype) and SW948 (KRAS mutant) xenograft mouse model. In vitro, cetuximab protected from hypoxia. In the LIM1215 model, a survival benefit with cetuximab and bevacizumab monotherapy was observed, but only the sequence CET->BEV showed an additional benefit. This effect was confirmed in the SW948 model. Our observations support the hypothesis that bevacizumab modulates the tumor microenvironment (e.g., by inducing hypoxia) where cetuximab could trigger protective effects when administered later on. The sequence CET->BEV therefore seems to be superior as possible mutual adverse effects are bypassed.
西妥昔单抗等靶向表皮生长因子受体（EGFR）的单克隆抗体以及贝伐单抗等靶向血管内皮生长因子（VEGF）的单克隆抗体，是转移性结直肠癌治疗方案的重要组成部分。然而，已证明抑制EGFR可在缺氧条件下保护人胶质瘤细胞免于细胞死亡。在结肠癌细胞中，缺氧状态下（如由贝伐单抗诱导）EGFR阻断的后果尚未得到评估。用西妥昔单抗、PD153035和厄洛替尼处理LIM1215和SW948结肠癌细胞以及LNT-229胶质母细胞瘤细胞，并分析细胞密度和活力。在LIM1215（KRAS野生型）和SW948（KRAS突变型）异种移植小鼠模型中研究了先给予西妥昔单抗后给予贝伐单抗（CET->BEV）或先给予贝伐单抗后给予西妥昔单抗（BEV->CET）的序贯给药方式。在体外，西妥昔单抗可保护细胞免受缺氧影响。在LIM1215模型中，观察到西妥昔单抗和贝伐单抗单药治疗有生存获益，但只有CET->BEV序列显示出额外的获益。这一效应在SW948模型中得到了证实。我们的观察结果支持这样的假设，即贝伐单抗可调节肿瘤微环境（如通过诱导缺氧），在此之后给予西妥昔单抗时可触发保护作用。因此，CET->BEV序列似乎更优，因为可能的相互不良反应被规避了。
