Eradication of Growth of HER2-Positive Ovarian Cancer With Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate in Mouse Xenograft Model
Eradication of Growth of HER2-Positive Ovarian Cancer With Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate in Mouse Xenograft Model
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DOI：
10.1097/igc.0000000000000179
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发表时间：
2014-09-01
影响因子：
4.8
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
--
作者：
Yu, Lin;Wang, Yuxi;Yang, Jinliang
目的：卵巢癌是一种高度恶性的妇科肿瘤，目前的治疗效果并不理想。人表皮生长因子受体2(HER2)Y靶向治疗包括曲妥珠单抗和曲妥珠单抗-DM1(T-DM1)(抗体-细胞毒药物结合物)已应用于临床治疗HER2过表达的乳腺癌。方法：检测6株卵巢癌细胞株和2株乳腺癌细胞株HER2的表达，并用流式细胞仪检测T-DM1与HER2阳性卵巢癌SKOV3细胞的结合能力。采用裸鼠腹膜内和皮下移植瘤模型，观察T-DM1的抗肿瘤作用。结果：HER2在SKOV3细胞系中呈高表达。T-DM1与HER2阳性的SKOV3细胞的结合能力与曲妥珠单抗相似。在体外，T-DM1对SKOV3细胞有很强的生长抑制作用，IC50值为0.15nmol/L。在皮下移植模型中，T-DM1(30 mg/kg和10 mg/kg)具有显著的抗癌作用。值得注意的是，T-DM1(30 mg/kg)组肿瘤被完全根除，在停止治疗后很长一段时间内没有再生长。在腹膜移植模型中，7只小鼠中有3只在腹腔内注射T-DM1(30 mg/kg)后，几乎没有发现肿瘤结节。结论：T-DM1对HER2过表达的小鼠卵巢癌模型具有良好的抗肿瘤作用，为进一步的临床试验提供了有价值的参考。
Objective: Ovarian cancer is 1 kind of a highly malignant gynecologic tumor, and current treatments have not achieved satisfactory effects. Human epidermal growth factor receptor 2 (HER2) Ytargeted therapies including trastuzumab and trastuzumab-DM1 (T-DM1) (antibody-cytotoxic drug conjugates) have been applied to treat HER2-overexpressing breast cancers in clinic. In the present study, we explored whether T-DM1 could effectively treat HER2-positive human ovarian carcinoma in vitro and in vivo.Methods: HER2 expressions of 6 ovarian cancer cell lines and 2 breast carcinoma cell lines were validated, and the binding capacity of T-DM1 to HER2-positive ovarian cancer SKOV3 cells were analyzed by flow cytometry. Nude mice bearing intraperitoneal and subcutaneous SKOV3 xenografts were used to investigate the antitumor effect of T-DM1.Results: High HER2 expressions in SKOV3 cell lines were detected. The binding capacity of T-DM1 to HER2-positive SKOV3 cells was in a similar manner comparing with trastuzumab. In vitro, T-DM1 showed strong growth inhibitory on SKOV3 cells, with IC50 values of 0.15 nmol/L. Nude mice bearing intraperitoneal and subcutaneous SKOV3 xenografts were used to investigate the antitumor effects of T-DM1 in vivo. In subcutaneous xenografts model, T-DM1 (30 mg/kg and 10 mg/kg) indicated significant anticancer effects. It is noteworthy that tumors were completely eradicated in the T-DM1 (30 mg/kg) group, and no regrowth was observed in a long time after the termination of the treatment. In the peritoneal xenograft model, tumor nodules in 3 of 7 mice were hardly observed in the abdominal cavity of mice after intraperitoneal injection of T-DM1 (30 mg/kg). At the same time, tumor nodules from the other 4 mice weighed on the average of only 0.07 g versus 1.77 g in control group.Conclusions: Our data showed that T-DM1 possessed promising antitumor effects on HER2-overexpressing ovarian cancer in mouse model, which provided valuable references for the future clinical trials.