Activity of anti-epidermal growth factor receptor monoclonal antibody C225 against glioblastoma multiforme
Activity of anti-epidermal growth factor receptor monoclonal antibody C225 against glioblastoma multiforme
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DOI：
10.1227/01.neu.0000029020.56466.17
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发表时间：
2002-10-01
期刊：
影响因子：
4.8
通讯作者：
Canute, GW
中科院分区：
文献类型：
--
作者：
Eller, JL;Longo, SL;Canute, GW
目的：继发于 EGFR 基因扩增的多形性胶质母细胞瘤 (GBM) 中表皮生长因子受体 (EGFR) 的过度表达与更具侵袭性的肿瘤表型和更差的临床结果相关。本研究的目的是分析用抗EGFR嵌合单克隆抗体C225阻断该受体是否会减少GBM细胞的增殖并增加细胞凋亡。方法：分析了七种人GBM细胞系的EGFR表达和扩增。然后将这些细胞系暴露于不同浓度的C225 48室、72小时和7天，之后在体外评估细胞毒性凋亡和血管内皮生长因子表达。将两个 EGFR 扩增的人 GBM 植入裸鼠的胁腹，动物腹膜内每周两次接受 C225，持续 5 周。将肿瘤体积和存活时间与假治疗小鼠的肿瘤体积和存活时间进行比较。 结果：EGFR 基因扩增在三个原发 GBM 系中得到证实：C225 治疗在所有三个 EGFR 扩增的 GBM 系中产生显着的细胞毒性，但在未扩增的系中不产生显着的细胞毒性。流式细胞术显示 C225 处理、EGFR 扩增的 GBM 系中细胞凋亡增加，但未扩增的细胞系中细胞凋亡没有增加。在暴露于 C225 的所有 GBM 系中，血管内皮生长因子表达均下降。用 C225 治疗的荷瘤小鼠的肿瘤生长受到显着抑制，中位生存期增加 200%。结论：在过表达该受体的 GBM 细胞中阻断 EGFR，可通过促进细胞凋亡同时减少增殖和血管内皮生长因子表达来显着改变肿瘤细胞生物学。这种方法为 GBM 患者的治疗带来了巨大的希望。
OBJECTIVE: Overexpression of epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) secondary to EGFR gene amplification is associated with a more aggressive tumor phenotype and a worse clinical outcome. The purpose of this study was to analyze whether blocking this receptor with the anti-EGFR chimeric monoclonal antibody C225 would decrease proliferation and increase apoptosis in GBM cells.METHODS: EGFR expression and amplification were analyzed for seven human GBM cell lines. These lines were then exposed to different concentration of C225 for 48 house, 72 hours, and 7 days, after which time cytotoxicity apoptosis, and vascular endothelial growth factor expression were assessed in vitro. Two EGFR-amplified human GBM were implanted in the flanks of nude mice, and the animals received C225 twice per week intraperitoneally for 5 weeks. Tumor volumes and survival times were compared with those of sham-treated mice.RESULTS: EGFR gene amplification was demonstrated in three of the primary GBM lines: C225 treatment produced significant cytotoxicity in all three EGFR-amplified GBM lines, but not in unamplified lines. Flow cytometry demonstrated increased apoptosis in C225-treated, EGFR-amplified GBM lines, but not in unamplified lines. There was a decrease in vascular in vascular endothelial growth factor expression in all GBM lines with exposure to C225. Tumor-bearing mice treated with C225 experienced significant inhibition of tumor growth as well as a 200% increase in median survival.CONCLUSION: Blocking EGFR in GBM cells that overexpress this receptor significantly changes tumor cell biology by promoting apoptosis while decreasing proliferation and vascular endothelial growth factor expression. This approach holds great promise for the treatment of patients with GBMs.