Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer
Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer
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DOI：
10.1016/j.canlet.2011.03.002
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发表时间：
2011-07-28
期刊：
影响因子：
9.7
通讯作者：
Isola, Jorma
中科院分区：
文献类型：
--
作者：
Barok, Mark;Tanner, Minna;Isola, Jorma
背景：一种新型抗体-药物偶联物（曲妥珠单抗-DM 1. T-DM 1）目前正在对曲妥珠单抗耐药的HER 2阳性乳腺癌患者进行临床试验。方法：采用体外培养的方法，研究T-DM 1对四种HER 2阳性胃癌细胞系（N-87、OE-19、SNU-216和MKN-7）的作用。结果：T-DM 1对N-87和OE-19的抑制作用强于曲妥珠单抗，对MKN-7细胞的抑制作用中等。在SNU-216细胞上，曲妥珠单抗和T-DM 1均显示出有限的功效。在异种移植肿瘤实验中，在所有OE-19异种移植小鼠和一半N-87异种移植小鼠中观察到完全病理学反应。无论治疗开始时或曲妥珠单抗治疗前的肿瘤负荷如何，结果均同样良好。T-DM 1处理显示直接效应（细胞凋亡和异常有丝分裂）以及其介导的抗体依赖性细胞毒性（ADCC）。结论：T-DM 1在体内外对HER 2阳性胃癌细胞系显示出有希望的抗肿瘤作用，即使在对曲妥珠单抗产生耐药性的肿瘤中也是如此。T-DM 1治疗可能需要对HER 2阳性胃癌患者进行临床试验。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Background: A novel antibody-drug conjugate (trastuzumab-DM1. T-DM1) is currently in clinical trials for patients with trastuzumab resistant HER2-positive breast cancer. Since no clinical data is available from gastric cancer, we studied T-DM1 on HER2-positive human gastric cancer cells and xenograft tumors.Methods: Effects of T-DM1 were studied in four HER2-positive gastric cancer cell lines (N-87, OE-19, SNU-216 and MKN-7) in vitro. Xenograft tumors from N-87 and OE-19 were studied to determine the effect of T-DM1 in vivo.Results: T-DM1 was found more effective than trastuzumab in N-87 and OE-19, and moderately effective in MKN-7 cells. On SNU-216 cells both trastuzumab and T-DM1 showed limited efficacy. In xenograft tumor experiments, complete pathological response was observed in all OE-19 xenografted mice and in half of the N-87 xenografted mice. The results were equally good irrespective of the tumor burden at therapy initiation, or preceding trastuzumab treatment. T-DM1 treatment showed direct effects (apoptotic cell death and aberrant mitosis) as well as it mediated antibody-dependent cellular cytotoxcity (ADCC).Conclusions: T-DM1 showed a promising anti-tumor effect in HER2-positive gastric cancer cell lines in vitro and in vivo, even in tumors which had developed resistance to trastuzumab. T-DM1 therapy may warrant clinical trials for HER2-positive gastric cancer patients. (C) 2011 Elsevier Ireland Ltd. All rights reserved.