Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Mol Cancer Ther. 2010 Jan;9(1):57-66. doi: 10.1158/1535-7163.MCT-09-0675. Epub 2010 Jan 6.
We evaluated the expression of epithelial cell adhesion molecule (EpCAM) and the potential of MT201 (adecatumumab), a human monoclonal antibody against EpCAM, in uterine serous papillary carcinoma (USPC). EpCAM expression was evaluated by real-time PCR and immunohistochemistry in a total of 56 USPC fresh-frozen biopsies and paraffin-embedded tissues. EpCAM surface expression was also evaluated by flow cytometry and immunohistochemistry in six USPC cell lines. Sensitivity to MT201 antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity was tested against a panel of primary USPC cell lines expressing different levels of EpCAM in standard 5-h (51)Cr release assays. EpCAM transcript was significantly overexpressed in fresh-frozen USPC when compared with normal endometrial cells (NEC). Median (minimum-maximum) copy number was 943.8 (31.5-1568.3) in tumor samples versus 12.9 (1.0-37.0) in NEC (P < 0.001). By immunohistochemistry, EpCAM expression was found in 96% (26 out of 27) of USPC samples with significantly higher expression compared with NECs (P < 0.001). High surface expression of EpCAM was found in 83% (five out of six) of the USPC cell lines tested by flow cytometry. EpCAM-positive cell lines were found highly sensitive to MT201-mediated antibody-dependent cellular cytotoxicity in vitro, whereas primary USPC cell lines were resistant to natural killer cell-dependent cytotoxicity. Human plasma IgG did not significantly inhibit MT201-mediated cytotoxicity against USPC. EpCAM is highly expressed in uterine serous carcinoma at mRNA and protein levels, and primary USPC are highly sensitivity to MT201-mediated cytotoxicity. MT201 might represent a novel therapeutic strategy in patients harboring advanced/recurrent or metastatic USPC refractory to standard treatment modalities.
我们评估了上皮细胞黏附分子（EpCAM）的表达和 MT201（adecatumumab）的潜力，MT201 是一种针对 EpCAM 的人源单克隆抗体，在子宫浆液性乳头状癌（USPC）中。通过实时 PCR 和免疫组织化学法，共评估了 56 例 USPC 新鲜冷冻活检和石蜡包埋组织中的 EpCAM 表达。还通过流式细胞术和免疫组织化学法，评估了 6 种 USPC 细胞系中 EpCAM 的表面表达。在标准的 5 小时（51）Cr 释放测定中，针对表达不同水平 EpCAM 的一系列原发性 USPC 细胞系，测试了 MT201 抗体依赖性细胞毒性和补体依赖性细胞毒性的敏感性。与正常子宫内膜细胞（NEC）相比，新鲜冷冻 USPC 中转录本 EpCAM 显著过表达。肿瘤样本的中位数（最小-最大）拷贝数为 943.8（31.5-1568.3），而 NEC 为 12.9（1.0-37.0）（P < 0.001）。通过免疫组织化学法，在 96%（27 例中有 26 例）的 USPC 样本中发现 EpCAM 表达，与 NEC 相比表达显著升高（P < 0.001）。通过流式细胞术检测，发现 83%（6 种 USPC 细胞系中的 5 种）的 USPC 细胞系中 EpCAM 高表达。在体外，EpCAM 阳性细胞系对 MT201 介导的抗体依赖性细胞毒性高度敏感，而原发性 USPC 细胞系对自然杀伤细胞依赖性细胞毒性具有抗性。人血浆 IgG 不能显著抑制 MT201 对 USPC 的细胞毒性。EpCAM 在 mRNA 和蛋白质水平上在子宫浆液性癌中高度表达，原发性 USPC 对 MT201 介导的细胞毒性高度敏感。MT201 可能代表一种新的治疗策略，用于治疗对标准治疗方案无效的晚期/复发性或转移性 USPC 患者。
