Pertuzumab in Combination with Trastuzumab Shows Significantly Enhanced Antitumor Activity in HER2-Positive Human Gastric Cancer Xenograft Models
Pertuzumab in Combination with Trastuzumab Shows Significantly Enhanced Antitumor Activity in HER2-Positive Human Gastric Cancer Xenograft Models
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DOI：
10.1158/1078-0432.ccr-10-2927
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发表时间：
2011-08-01
影响因子：
11.5
通讯作者：
Fujimoto-Ouchi, Kaori
中科院分区：
文献类型：
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作者：
Yamashita-Kashima, Yoriko;Iijima, Shigeyuki;Fujimoto-Ouchi, Kaori
目的：我们研究了两种不同的人源化单克隆人表皮生长因子受体（HER）2抗体（帕妥珠单抗和曲妥珠单抗）组合对胃癌的抗肿瘤活性。实验设计：使用肿瘤小鼠异种移植模型来检查抗肿瘤活性。使用结晶紫染色检查细胞增殖。通过ELISA和免疫组织化学分析HER家族蛋白的表达。分别通过蛋白质印迹和原位邻近连接测定（PLA）检测磷酸化蛋白和异二聚体。通过半胱天冬酶 3/7 活性检查细胞凋亡活性。 xCELLigence 检测抗体依赖性细胞毒性 (ADCC) 活性。通过 CD31 染色检查微血管密度。结果：在 HER2 阳性人胃癌异种移植模型 NCI-N87 中，帕妥珠单抗联合曲妥珠单抗与单药治疗相比显示出显着的抗肿瘤活性。疗效强于每种单一疗法的最大有效剂量。另一种 HER2 阳性胃癌模型 4-1ST 中也显示出类似的抗肿瘤活性，但 HER2 阴性模型 MKN-28 中则没有显示出类似的抗肿瘤活性。帕妥珠单抗与曲妥珠单抗联合使用可通过抑制 EGFR-HER2 异二聚化以及这些受体及其下游因子的磷酸化来增强细胞生长抑制和凋亡活性。这种效应也出现在 HER2-HER3 信号传导中。此外，帕妥珠单抗与曲妥珠单抗联合增强了这些抗体的 ADCC 活性，并降低了肿瘤微血管密度。结论：我们通过增强细胞生长抑制、凋亡活性、ADCC 的细胞杀伤活性和抗血管生成活性，证明帕妥珠单抗与曲妥珠单抗联合治疗 HER2 过表达胃癌的疗效显着增强。这项研究表明帕妥珠单抗和曲妥珠单抗联合治疗对 HER2 阳性胃癌患者具有临床益处。临床癌症研究； 17(15)； 5060-70。 (C)2011 AACR。
Purpose: We investigated the antitumor activity of the combination of two different humanized monoclonal human epidermal growth factor receptor (HER) 2 antibodies, pertuzumab and trastuzumab, for gastric cancer.Experimental Design: Tumor mouse xenograft models were used to examine antitumor activity. Cell proliferation was examined using crystal violet staining. HER family proteins' expression was analyzed by ELISA and immunohistochemistry. Phosphorylated proteins and heterodimers were detected by Western blotting and in situ proximity ligation assay (PLA), respectively. Apoptosis activity was examined by caspase 3/7 activity. Antibody-dependent cellular cytotoxicity (ADCC) activity was detected by xCELLigence. Microvessel density was examined by CD31 staining.Results: Pertuzumab in combination with trastuzumab showed significant antitumor activity compared with each monotherapy in NCI-N87, an HER2-positive human gastric cancer xenograft model. The efficacy was stronger than that of the maximum effective dose with each monotherapy. Similar antitumor activity was shown in 4-1ST, another HER2-positive gastric cancer model, but not in MKN-28, an HER2-negative model. Combining pertuzumab with trastuzumab enhanced cell growth inhibition and apoptosis activity by inhibiting EGFR-HER2 heterodimerization and the phosphorylation of these receptors and their downstream factors. This effect was also seen in HER2-HER3 signaling. Furthermore, pertuzumab in combination with trastuzumab potentiated the ADCC activity of those antibodies and reduced tumor microvessel density.Conclusions: We showed the significantly enhanced efficacy of pertuzumab combining with trastuzumab for HER2 overexpressing gastric cancer through the potentiation of cell growth inhibition, apoptosis activity, cell killing activity by ADCC, and antiangiogenic activity. This study suggests the clinical benefit of combination therapy with pertuzumab and trastuzumab for patients with HER2-positive gastric cancers. Clin Cancer Res; 17(15); 5060-70. (C)2011 AACR.