Tonra James R, Deevi Dhanvanthri S, Corcoran Erik, Li Huiling, Wang Su, Carrick Francine E, Hicklin Daniel J
ImClone Systems Inc., New York, New York, USA.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2197-207. doi: 10.1158/1078-0432.CCR-05-1682.
Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer. In evaluating combination strategies, the ideal combination would be one in which the treatments interact in a way that is synergistic with regard to antitumor effects. Here, we have evaluated the interaction between anti-EGFR antibody Erbitux (cetuximab) and anti-VEGFR2 antibody, DC101, in preclinical models of pancreatic (BxPC-3) and colon (GEO) cancer.
Analysis of the interaction between cetuximab and DC101 in vivo used a novel method for establishing the upper 95% confidence limits for the combination index (CI) of isobologram analyses, where CI < 1 indicates synergy. Assessment of tumor cell proliferation, apoptosis, VEGF production, and hypoxia, as well as tumor vascularization, was performed to gain insights into the mechanistic basis for synergy between agents targeting different tumor compartments.
Monotherapy ED(50) values for tumor growth inhibition ranged from 1.8 to 2.3 mg/kg and 10.5 to 16.6 mg/kg for cetuximab and DC101, respectively. From the dose response of the combination treatment, it was determined that cetuximab and DC101 are synergistic in the BxPC-3 (CI = 0.1, P < 0.01) and GEO (CI = 0.1, P < 0.01) models. Overlapping effects on the tumor cell and vascular compartments form a basis for the interaction, with VEGF production and hypoxia-inducible factor 1alpha potentially acting as molecular links between EGFR and VEGFR2 inhibition.
Results show antitumor synergy for combined EGFR and VEGFR2 targeted therapy, supporting the significant therapeutic potential of this combination strategy.
针对表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGFR）途径的联合疗法正在积极地进行癌症治疗测试。在评估联合策略时，理想的联合疗法应是两种治疗方法在抗肿瘤作用方面以协同方式相互作用。在此，我们在胰腺癌（BxPC-3）和结肠癌（GEO）的临床前模型中评估了抗EGFR抗体爱必妥（西妥昔单抗）与抗VEGFR2抗体DC101之间的相互作用。
体内西妥昔单抗与DC101相互作用的分析采用了一种新方法，用于确定等效线分析联合指数（CI）的上95%置信限，其中CI < 1表示协同作用。对肿瘤细胞增殖、凋亡、VEGF产生、缺氧以及肿瘤血管生成进行评估，以深入了解针对不同肿瘤区域的药物之间协同作用的机制基础。
西妥昔单抗和DC101对肿瘤生长抑制的单药治疗ED(50)值分别为1.8至2.3 mg/kg和10.5至16.6 mg/kg。从联合治疗的剂量反应来看，确定西妥昔单抗和DC101在BxPC-3（CI = 0.1，P < 0.01）和GEO（CI = 0.1，P < 0.01）模型中具有协同作用。对肿瘤细胞和血管区域的重叠作用构成了相互作用的基础，VEGF产生和缺氧诱导因子1α可能作为EGFR和VEGFR2抑制之间的分子联系。
结果显示EGFR和VEGFR2靶向联合治疗具有抗肿瘤协同作用，支持了这种联合策略的巨大治疗潜力。
