Department of Surgery, Charité-School of Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.
Gastric Cancer. 2012 Jul;15(3):252-64. doi: 10.1007/s10120-011-0102-9. Epub 2011 Oct 20.
Targeting the epidermal growth factor receptor (EGFR) pathway is an important approach for a variety of tumors. This study assessed the effect of cetuximab, an anti-EGFR monoclonal antibody, on three gastric cancer cell lines with different phenotypes in vitro and in a therapeutic orthotopic murine gastric cancer model.
Three human gastric cancer cell lines (AGS, MKN-45, NCI-N87) were evaluated for cell surface EGFR expression, and K-ras and BRAF mutations. In vitro, the effects of cetuximab, carboplatin, irinotecan, and docetaxel were investigated. Orthotopic tumors derived from MKN-45 and NCI-N87 were established in nude mice. After 4 weeks, the animals received cetuximab (1 mg/kg, weekly i.p.) or carboplatin (20 mg/kg, weekly i.p.), or both agents. The volume of the primary tumor and local and systemic tumor spread were determined at autopsy at 14 weeks. Tumor sections were immunostained for EGFR, as well as stained for CD31 to analyze microvessel density.
Cell surface expression of EGFR was found only in AGS and NCI-N87 cells. AGS cells displayed a codon 12 K-ras mutation, and all three cell lines were BRAF wild-type. In vitro, cetuximab significantly reduced cell viability and proliferation only in EGFR-positive/K-ras wild-type NCI-N87 cells (-48%). In vivo, cetuximab in combination with carboplatin synergistically reduced tumor volume (-75%), dissemination (-63%), and vascularization (-47%) in NCI-N87 xenografts. Tumors derived from EGFR-negative MKN-45 cells were unaffected by cetuximab.
Cetuximab is effective in K-ras wild-type, EGFR-expressing gastric cancer cell lines and xenografts. In vivo, the combination of cetuximab with carboplatin displayed synergistic antitumor activity.
靶向表皮生长因子受体（EGFR）途径是多种肿瘤的重要治疗方法。本研究评估了抗 EGFR 单克隆抗体西妥昔单抗在体外和治疗性原位胃癌小鼠模型中对三种具有不同表型的胃癌细胞系的作用。
评估了三种人胃癌细胞系（AGS、MKN-45、NCI-N87）的细胞表面 EGFR 表达、K-ras 和 BRAF 突变。在体外，研究了西妥昔单抗、卡铂、伊立替康和多西他赛的作用。在裸鼠中建立了源自 MKN-45 和 NCI-N87 的原位肿瘤。4 周后，动物接受西妥昔单抗（1mg/kg，每周腹腔注射）或卡铂（20mg/kg，每周腹腔注射）或两者联合治疗。14 周时解剖测量原发性肿瘤的体积以及局部和全身肿瘤转移情况。肿瘤切片免疫染色 EGFR，并用 CD31 染色分析微血管密度。
仅在 AGS 和 NCI-N87 细胞中发现细胞表面 EGFR 表达。AGS 细胞显示 12 密码子 K-ras 突变，三种细胞系均为 BRAF 野生型。在体外，西妥昔单抗仅在 EGFR 阳性/K-ras 野生型 NCI-N87 细胞中显著降低细胞活力和增殖（-48%）。在体内，西妥昔单抗联合卡铂协同减少 NCI-N87 异种移植瘤的体积（-75%）、播散（-63%）和血管生成（-47%）。EGFR 阴性的 MKN-45 细胞来源的肿瘤不受西妥昔单抗影响。
西妥昔单抗对 K-ras 野生型、EGFR 表达的胃癌细胞系和异种移植瘤有效。在体内，西妥昔单抗联合卡铂显示出协同的抗肿瘤活性。
