hEGF 摄取量的显著增加与 EGFR 酪氨酸激酶抑制剂吉非替尼诱导的 EGFR 二聚体的形成相关。

Significant increase in hEGF uptake is correlated with formation of EGFR dimers induced by the EGFR tyrosine kinase inhibitor gefitinib.

机构信息

Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, People's Republic of China.

出版信息

Cancer Chemother Pharmacol. 2013 Aug;72(2):341-8. doi: 10.1007/s00280-013-2198-6. Epub 2013 Jun 8.

PURPOSE

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) is approved for cancer treatment. We investigated whether gefitinib treatment can enhance human EGF (hEGF) uptake in vitro, thereby increasing the potential of hEGF as a vehicle for EGFR-targeted therapy.

METHODS

Western blotting was used to detect the effect of gefitinib on EGFR signaling. Different EGFR-expressing tumor cells (SCC-1, 22B, A549, and HT-29) were pretreated with gefitinib, and then with (125)I-hEGF or (125)I-Vectibix (an anti-EGFR monoclonal antibody). Cell-associated activity was then measured. A cross-linking assay detected increased EGFR dimer formation in gefitinib-treated cells.

RESULTS

Total EGFR levels were not changed, but EGFR phosphorylation was reduced in cells pretreated with gefitinib. Gefitinib mediated formation of EGFR dimers; binding of (125)I-hEGF to cells pretreated with gefitinib significantly increased. In contrast, binding of (125)I-Vectibix to tumor cells did not increase. Although total EGFR levels did not increase, binding of hEGF to EGFR + tumors was significantly enhanced after gefitinib treatment, because of increased hEGF binding to gefitinib-induced EGFR dimers.

CONCLUSION

These results suggest that hEGF could enhance EGFR-targeting when used with gefitinib.

目的

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼（ZD1839，易瑞沙）已被批准用于癌症治疗。我们研究了吉非替尼治疗是否能增强体外人表皮生长因子（hEGF）的摄取，从而增加 hEGF 作为 EGFR 靶向治疗载体的潜力。

方法

使用 Western blot 检测吉非替尼对 EGFR 信号的影响。用吉非替尼预处理不同 EGFR 表达的肿瘤细胞（SCC-1、22B、A549 和 HT-29），然后用（125）I-hEGF 或（125）I-Vectibix（一种抗 EGFR 单克隆抗体）。然后测量细胞相关活性。交联试验检测到吉非替尼处理细胞中 EGFR 二聚体形成增加。

结果

总 EGFR 水平没有变化，但 EGFR 磷酸化在吉非替尼预处理的细胞中减少。吉非替尼介导 EGFR 二聚体形成；（125）I-hEGF 与吉非替尼预处理细胞的结合显著增加。相比之下，（125）I-Vectibix 与肿瘤细胞的结合没有增加。尽管总 EGFR 水平没有增加，但 hEGF 与 EGFR+肿瘤的结合在吉非替尼治疗后显著增强，因为 hEGF 与吉非替尼诱导的 EGFR 二聚体结合增加。