PET of EGFR antibody distribution in head and neck squamous cell carcinoma models.
PET of EGFR antibody distribution in head and neck squamous cell carcinoma models.
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DOI：
10.2967/jnumed.109.061820
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Niu G;Li Z;Xie J;Le QT;Chen X
表皮生长因子受体(EGFR)是一种具有良好特性的原癌基因，已被证明在实体癌中促进肿瘤的进展。用西妥昔单抗和Panitumab等特异性单抗靶向EGFR的临床结果令人振奋；然而，大多数研究表明，只有一小部分接受单抗的患者从免疫治疗中受益，与EGFR的表达水平无关。为了了解抗体传递和定位的体内动力学，我们用64Cu标记的Panitumumab在来自3个人头颈部鳞状细胞癌(HNSCC)细胞系的异种移植瘤中进行了小动物PET研究。用64Cu-1，4，7，10-四氮杂环十二烷-N，N‘，N“，N”，N-‴-四乙酸单抗对荷瘤裸鼠进行小动物显像。用Panitumab和荧光素5-异硫氰酸酯(FITC)Panitumab体外免疫染色证实抗体在肿瘤中的分布。CD31免疫组织化学染色和伊文思蓝染色检测肿瘤血管密度和通透性。在这3种肿瘤模型中，EGFR蛋白表达最低的UM-SCC-22B肿瘤的64CuDOTA-panitumab积聚最高，而EGFR表达最高的SQB20肿瘤的64CuDOTA-panitumumab积聚最低。体外染色显示，SQB20细胞在裸鼠体内成瘤后仍有极高的EGFR表达，表明SQB20肿瘤对64CuDOTA-panitumab的低摄取不是由于EGFR表达缺失所致。CD31免疫染色和伊文思蓝渗透试验结果表明，低血管密度、低血管通透性和结合部位屏障可能是高表达EGFR的SQB20肿瘤整体摄取低的原因。这项研究的结果可能解释了西妥昔单抗和Panitumab的疗效与免疫组织化学或荧光原位杂交检测的EGFR表达水平之间缺乏相关性的原因，并可能为抗EGFR单抗治疗HNSCC和其他恶性肿瘤的并发症提供新的线索。
Epidermal growth factor receptor (EGFR) is a well-characterized protooncogene that has been shown to promote tumor progression in solid cancers. Clinical results for EGFR targeting with specific monoclonal antibodies (mAbs) such as cetuximab and panitumumab are promising; however, most studies indicate that only a subgroup of patients receiving the mAbs benefit from the immunotherapy, independent of EGFR expression level. To understand the in vivo kinetics of antibody delivery and localization, we performed small-animal PET studies with 64Cu-labeled panitumumab in xenografts derived from 3 cell lines of human head and neck squamous cell carcinoma (HNSCC). Nude mice bearing HNSCC tumors with different levels of EGFR expression were imaged with small-animal PET using 64Cu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-panitumumab. Antibody distribution in the tumors was confirmed by ex vivo immunostaining using panitumumab and fluorescein 5-isothiocyanate (FITC) panitumumab. CD31 immunostaining and Evans blue assay were also performed to assess the tumor vascular density and permeability. Among these 3 tumor models, UM-SCC-22B tumors with the lowest EGFR protein expression showed the highest 64Cu-DOTA-panitumumab accumulation, whereas SQB20 tumors with the highest EGFR expression showed the lowest 64Cu-DOTA-panitumumab accumulation. Ex vivo staining demonstrated that SQB20 cells still had extremely high EGFR expression after forming tumors in nude mice, indicating that the low uptake of 64Cu-DOTA-panitumumab in SQB20 tumors was not due to the loss of EGFR expression. The results from CD31 immunostaining and Evans blue permeability assay suggest that the low vessel density, poor vascular permeability, and binding site barrier are likely responsible for the overall low tumor uptake of the highly EGFR-expressing SQB20 tumors. The results from this study provide a possible explanation for the lack of an observed correlation between therapeutic efficacy of cetuximab and panitumumab and EGFR expression level as determined by immunohistochemistry or fluorescent in situ hybridization and may shed new light on the complications of anti-EGFR mAb therapy for HNSCC and other malignancies.
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