曲妥珠单抗-DM1 在 HER2 阳性胃癌的临床前模型中具有高度疗效。
Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer.
机构信息
Institute of Medical Technology, University of Tampere, Tampere, Finland.
出版信息
Cancer Lett. 2011 Jul 28;306(2):171-9. doi: 10.1016/j.canlet.2011.03.002. Epub 2011 Apr 1.
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 cytotoxicity (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.
背景
一种新型抗体药物偶联物（曲妥珠单抗-DM1，T-DM1）目前正在进行临床试验，用于治疗曲妥珠单抗耐药的 HER2 阳性乳腺癌患者。由于尚无胃癌的临床数据，我们研究了 T-DM1 对 HER2 阳性人胃癌细胞和异种移植瘤的作用。
方法
我们在四种 HER2 阳性胃癌细胞系（N-87、OE-19、SNU-216 和 MKN-7）中研究了 T-DM1 的作用。我们研究了 N-87 和 OE-19 的异种移植瘤，以确定 T-DM1 的体内作用。
结果
T-DM1 在 N-87 和 OE-19 中的作用比曲妥珠单抗更有效，在 MKN-7 细胞中作用中等。在 SNU-216 细胞中，曲妥珠单抗和 T-DM1 的作用均有限。在异种移植瘤实验中，所有 OE-19 异种移植瘤小鼠和一半 N-87 异种移植瘤小鼠均观察到完全病理缓解。无论治疗开始时的肿瘤负荷如何，或者是否进行过曲妥珠单抗治疗，结果都一样好。T-DM1 治疗不仅具有直接作用（凋亡细胞死亡和异常有丝分裂），还介导抗体依赖性细胞毒性（ADCC）。
结论
T-DM1 在体外和体内对 HER2 阳性胃癌细胞系表现出有希望的抗肿瘤作用，即使在对曲妥珠单抗耐药的肿瘤中也是如此。T-DM1 治疗可能需要对 HER2 阳性胃癌患者进行临床试验。
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