T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo.
T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo.
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DOI：
10.1002/cam4.274
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发表时间：
2014-10
期刊：
影响因子：
4
通讯作者：
Santin, Alessandro D.
中科院分区：
文献类型：
--
作者：
English, Diana P.;Bellone, Stefania;Schwab, Carlton L.;Bortolomai, Ileana;Bonazzoli, Elena;Cocco, Emiliano;Buza, Natalia;Hui, Pei;Lopez, Salvatore;Ratner, Elena;Silasi, Dan-Arin;Azodi, Masoud;Schwartz, Peter E.;Rutherford, Thomas J.;Santin, Alessandro D.
据报道，超过 30% 的子宫浆液性癌 (USC) 中存在 c-erbB2 扩增，并且由于高增殖和治疗耐药性增加，导致生存率较差。在这项研究中，我们首次在体外评估了曲妥珠单抗 emtansine (T-DM1)（一种新型抗体药物偶联物）对多种表皮生长因子受体 2 (HER2) 阳性 USC 细胞的作用，随后开发了支持性体内模型。通过免疫组织化学 (IHC) 和流式细胞术评估 15 个原代 USC 细胞系的 HER2 蛋白表达。使用荧光原位杂交评估C-erbB2基因扩增。在 5 小时铬释放测定中评估对 T-DM1 和曲妥珠单抗 (T) 诱导的抗体依赖性细胞介导的细胞毒性的敏感性。使用基于流式细胞术的增殖测定来评估 T-DM1 和 T 细胞抑制和凋亡活性。还评估了 SCID 小鼠 USC 异种移植物中 T-DM1 与 T 的体内活性。在 33% 的 USC 细胞系中检测到高水平的 HER2 蛋白过表达和 HER2 基因扩增。 T-DM1 在抑制细胞增殖和引起显示 HER2 过度表达的 USC 细胞凋亡方面比曲妥珠单抗更有效（P = 0.004）。重要的是，在过度表达 HER2 的 USC 异种移植物中，T-DM1 在减少体内肿瘤形成方面具有高度活性（P = 0.04），并且与 T 治疗小鼠和对照小鼠相比，用 TDM-1 治疗的小鼠的生存期显着更长（P ≤ 0.0001）。 T-DM1 在 HER2 阳性 USC 细胞系和 USC 异种移植物中显示出有希望的抗肿瘤作用，并且与 T 相比，其活性显着更高。T-DM1 可能代表对曲妥珠单抗和传统化疗耐药的 HER2 阳性 USC 患者的一种新的治疗选择。
Amplification of c-erbB2 has been reported in over 30% of uterine serous carcinoma (USC) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody–drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry (IHC) and flow cytometry for HER2 protein expression. C-erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T-DM1 and trastuzumab (T)-induced antibody-dependent cell-mediated cytotoxicity was evaluated in 5-h chromium release assays. T-DM1 and T cytostatic and apoptotic activities were evaluated using flow-cytometry-based proliferation assays. In vivo activity of T-DM1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER2 protein overexpression and HER2 gene amplification were detected in 33% of USC cell lines. T-DM1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis (P = 0.004) of USC showing HER2 overexpression. Importantly, T-DM1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER2 (P = 0.04) and mice treated with TDM-1 had significantly longer survival when compared to T-treated mice and control mice (P ≤ 0.0001). T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to trastuzumab and traditional chemotherapy.
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DOI：
10.1111/j.1525-1438.2006.00664.x
发表时间：
2006-09-01
影响因子：
4.8
作者：
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通讯作者：
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