Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
Br J Cancer. 2010 Jan 5;102(1):134-43. doi: 10.1038/sj.bjc.6605448. Epub 2009 Nov 17.
Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu.
Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays.
Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression.
Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.
子宫浆液性乳头状腺癌（USPC）是一种罕见但高度侵袭性的子宫内膜癌变体。曲妥珠单抗是一种针对表皮生长因子受体 2（HER2/neu）的新型人源化单克隆抗体（mAb）。我们评估了曲妥珠单抗单独或联合使用对表达不同水平 HER2/neu 的原发性 USPC 细胞系的活性。
通过免疫组织化学（IHC）、流式细胞术和实时 PCR 评估 6 种 USPC 细胞系的 HER2/neu 表达。使用荧光原位杂交（FISH）评估 c-erbB2 基因扩增。使用 51Cr 释放试验评估对 pertuzumab 和 trastuzumab 诱导的抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）的敏感性。使用基于增殖的测定法评估 pertuzumab 的细胞抑制活性。
3 种 USPC 细胞系通过 IHC 强烈染色 HER2/neu，并通过 FISH 显示 c-erbB2 基因扩增。其余 FISH 阴性的 USPC 表达 0/1+水平的 HER2/neu。在针对高 HER2/neu 表达的 USPC 的细胞毒性实验中，pertuzumab 和 trastuzumab 在诱导强烈 ADCC 方面同样有效。添加含有补体的血浆和白细胞介素 2 增加了两种 mAb 诱导的细胞毒性作用。在低 HER2/neu USPC 表达者中，trastuzumab 比 pertuzumab 更能诱导 ADCC。重要的是，在这种情况下，pertuzumab 与 trastuzumab 的联合使用显著增加了 trastuzumab 单独诱导的 ADCC 效应（P=0.02）。最后，pertuzumab 抑制了所有测试的 USPC 细胞系的增殖，无论其 HER-2/neu 表达如何。
pertuzumab 和 trastuzumab 在 FISH 阳性的 USPC 细胞系中诱导同等强度的 ADCC 和 CDC。pertuzumab 显著增加了对低 HER2/neu 表达的 USPC 中 trastuzumab 诱导的 ADCC，可能是治疗晚期/复发性和/或难治性 USPC 患者的新治疗药物。
