Herceptin down-regulates HER-2/neu and vascular endothelial growth factor expression and enhances taxol-induced cytotoxicity of human Ewing's sarcoma cells in vitro and in vivo
Herceptin down-regulates HER-2/neu and vascular endothelial growth factor expression and enhances taxol-induced cytotoxicity of human Ewing's sarcoma cells in vitro and in vivo
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DOI：
10.1158/1078-0432.ccr-04-0777
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发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Kleinerman, ES
中科院分区：
文献类型：
--
作者：
Guan, H;Jia, SF;Kleinerman, ES
我们之前的研究表明，相对于正常的人成骨细胞，HER-2/neu蛋白在人尤文氏肉瘤细胞（TC71, SK-ES1）中高水平过表达。本研究的目的是确定赫赛汀单独或联合化疗药物是否能在体外和体内抑制尤文氏肉瘤的生长。Western blot分析显示HER2/neu蛋白水平在赫赛汀治疗后降低。赫赛汀对TC71和SK-ES1细胞株的细胞生长也有抑制作用，且呈剂量依赖性，IC50为4 mg/mL，而人免疫球蛋白对细胞生长无影响。Northern blot和ELISA结果显示，赫赛汀也抑制了血管内皮生长因子的RNA表达和蛋白水平，但hif -1 α蛋白和拓扑异构酶iα的表达没有改变。此外，在我们的Ewing肉瘤异种移植小鼠模型中，100 mg/kg赫赛汀治疗明显延迟了Ewing肉瘤肿瘤的生长。紫杉醇和赫赛汀联合使用会导致细胞毒性的增加，而赫赛汀-依托泊苷、阿霉素和9-硝基喜树碱联合使用则不会。与单独使用两种药物相比，紫杉醇-赫赛汀增强了体外TC71细胞的生长抑制作用。在体内，Ewing肉瘤的生长也被延迟，接受赫赛汀加紫杉醇治疗的小鼠的平均肿瘤大小明显低于单独接受紫杉醇或赫赛汀治疗的小鼠。这些数据表明，赫赛汀联合紫杉醇可能是治疗尤文氏肉瘤的一种治疗选择。
We have previously shown that high levels of HER-2/neu protein were overexpressed in human Ewing's sarcoma cells (TC71, SK-ES1) relative to normal human osteoblasts. The purpose of this study was to determine whether herceptin alone or in combination with chemotherapeutic agents could inhibit the growth of Ewing's sarcoma in vitro and in vivo. Western blot analysis showed that the protein levels of HER2/neu were decreased following herceptin treatment. Cell growth was also inhibited by herceptin in a dose-dependent manner with an IC50 of 4 mg/mL in TC71 and SK-ES1 cell line, whereas human immunoglobin had no effect. Northern blot and ELISA showed the RNA expression and protein levels of vascular endothelial growth factor were also inhibited by herceptin treatment with no alteration in HIF-1alpha protein and topoisomerase IIalpha expression. Furthermore, Ewing's sarcoma tumor growth was significantly delayed by 100 mg/kg herceptin treatment in our Ewing's sarcoma xenograft mouse model. Combining taxol with herceptin resulted in additive cytotoxicity, whereas herceptin-etoposide, doxorubicin, and 9-nitrocamptothecin combinations did not. Taxol-herceptin enhanced growth inhibition in TC71 cells in vitro compared with either agent alone. Ewing's sarcoma growth was also delayed in vivo and mean tumor size was significantly lower in mice treated with herceptin plus taxol than in those receiving taxol or herceptin alone. These data suggest that herceptin in combination with taxol may be a therapeutic option in the treatment of Ewing's sarcoma.