Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Int J Cancer. 2013 Jul 15;133(2):307-14. doi: 10.1002/ijc.28046. Epub 2013 Feb 15.
Bevacizumab (antivascular endothelial growth factor [anti-VEGF]) and cetuximab (antiepidermal growth factor receptor [anti-EGFR]) are approved antibodies for treatment of cancer. However, in advanced colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, our study aims to determine the effect of bevacizumab on targeting of anti-EGFR and insulin-like growth factor 1 receptor (IGF-1R) antibodies in tumors with single-photon emission computed tomography (SPECT)/CT imaging. Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts received a single dose of bevacizumab (10 mg/kg) or saline. After 4 days, mice were injected with radiolabeled cetuximab or R1507, an anti-IGF-1R antibody. A control group received a radiolabeled irrelevant IgG (hLL2). Three days later, SPECT/CT images were acquired and mice were dissected to determine the concentration of antibodies in the tissues. Tumors were analyzed immunohistochemically to determine vascular density (CD34), VEGF, EGFR and IGF-1R expression. SPECT/CT imaging revealed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled cetuximab by 40% from 33.1 ± 1.1 %ID/g to 19.8 ± 5.7 %ID/g (p = 0.009) for untreated and bevacizumab-treated tumors, respectively. A similar effect was found for (111) In-R1507: tumor targeting of R1507 decreased by 35%. No significant differences in tumor uptake were observed in mice that received an irrelevant IgG. Uptake in normal organs was not altered by bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, whereas EGFR and IGF-1R expression was unaltered. In conclusion, bevacizumab treatment significantly reduces tumor targeting of anti-EGFR and anti-IGF-1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies.
贝伐单抗（血管内皮生长因子 [抗-VEGF]）和西妥昔单抗（表皮生长因子受体 [抗-EGFR]）是批准用于治疗癌症的抗体。然而，在晚期结直肠癌中，联合治疗未能改善生存率。由于缺乏活性的原因尚不清楚，我们的研究旨在通过单光子发射计算机断层扫描（SPECT）/CT 成像确定贝伐单抗对肿瘤中抗 EGFR 和胰岛素样生长因子 1 受体（IGF-1R）抗体靶向的影响。皮下表达 EGFR 和 IGF-1R 的 SUM149 异种移植小鼠接受单次贝伐单抗（10mg/kg）或生理盐水治疗。4 天后，小鼠注射放射性标记的西妥昔单抗或 R1507（抗 IGF-1R 抗体）。对照组接受放射性标记的无关 IgG（hLL2）。3 天后，进行 SPECT/CT 成像，并对小鼠进行解剖以确定组织中的抗体浓度。对肿瘤进行免疫组织化学分析以确定血管密度（CD34）、VEGF、EGFR 和 IGF-1R 表达。SPECT/CT 成像显示，贝伐单抗治疗使未经处理和贝伐单抗处理的肿瘤中放射性标记的西妥昔单抗的肿瘤靶向性分别降低了 40%，从 33.1±1.1%ID/g 降至 19.8±5.7%ID/g（p=0.009）。对于（111）In-R1507 也观察到类似的效果：R1507 的肿瘤靶向性降低了 35%。接受无关 IgG 的小鼠肿瘤摄取无明显差异。贝伐单抗不改变正常器官的摄取。免疫组织化学分析显示，血管密度降低了 43%，而 EGFR 和 IGF-1R 表达未改变。总之，贝伐单抗治疗显著降低了抗 EGFR 和抗 IGF-1R 抗体的肿瘤靶向性。这强调了贝伐单抗与其他抗体联合使用时的时机和顺序的重要性。
