Imaging Sciences Training Program, Radiology and Imaging Sciences, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD20892, USA.
Clin Cancer Res. 2010 Apr 1;16(7):2095-105. doi: 10.1158/1078-0432.CCR-09-2495. Epub 2010 Mar 9.
To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.
EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.
EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.
Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.
通过定量正电子发射断层扫描（PET）成像，研究表皮生长因子受体（EGFR）靶向免疫治疗和放射免疫治疗中的抗体递送与治疗效果的关系。
通过流式细胞术和免疫染色确定 UM-SCC-22B 和 SCC1 人头颈部鳞状细胞癌（HNSCC）细胞上的 EGFR 表达。使用小动物 PET 评估荷瘤裸鼠中西妥昔单抗的递送和分布情况，使用（64）Cu-DOTA-西妥昔单抗。通过 MTT 测定评估西妥昔单抗对 HNSCC 细胞的体外毒性。然后，用 10mg/kg 剂量的西妥昔单抗治疗四剂，并用卡尺测量评估肿瘤生长。在第三次抗体给药后进行 FDG PET 以评估肿瘤反应。用末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记和 Ki-67 染色分析西妥昔单抗治疗后的细胞凋亡和肿瘤细胞增殖。用（90）Y-DOTA-西妥昔单抗进行放射免疫治疗。
UM-SCC-22B 细胞上的 EGFR 表达低于 SCC1 细胞。然而，UM-SCC-22B 肿瘤的（64）Cu-DOTA-西妥昔单抗积累明显高于 SCC1 肿瘤。西妥昔单抗诱导 SCC1 肿瘤细胞凋亡并显著抑制肿瘤生长，而对 UM-SCC-22B 肿瘤生长则具有激动作用。西妥昔单抗治疗后，SCC1 肿瘤的 FDG 摄取减少，而 UM-SCC-22B 肿瘤的 FDG 摄取增加。与 SCC1 肿瘤相比，UM-SCC-22B 肿瘤对（90）Y-DOTA-西妥昔单抗治疗的反应更高，部分原因是注射抗体的高肿瘤积累。
西妥昔单抗对 UM-SCC-22B 肿瘤的生长具有激动作用，表明肿瘤对西妥昔单抗治疗的反应不一定与 PET 成像确定的 EGFR 表达和抗体递送效率相关。尽管作为示踪剂的抗体 PET 成像在患者筛选中具有有限的功能，但它可以为使用抗体作为递送载体的靶向治疗提供指导。
