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目的建立EGFRIs(吉非替尼)耐药的EGFR野生型移植瘤模型,并研究其可能耐药机制。方法雌性BALB/c裸鼠皮下注射A431细胞,肿瘤生长到150×200mm~3,口服给予50mg/kg的吉非替尼,1次/d,连续25周后对EGFRIs产生耐药。比较敏感和耐药移植瘤的全基因组基因表达谱寻找目的基因。耐药模型分别接受空白对照组、吉非替尼、目的基因抑制剂(AMG706),或它们的混合物治疗21d,检测肿瘤组织生长、细胞凋亡、目的基因以及相关细胞因子表达情况。结果 C-kit在吉非替尼耐药的A431异种移植瘤中过表达,双重阻断EGFR和c-Kit信号有协同作用,引起细胞凋亡。结论 A431异种移植瘤模型中诱导的吉非替尼耐药可能与c-Kit过表达有关。EGFRIs和c-Kit抑制剂的联合治疗可能阻断这种耐药机制,抑制肿瘤细胞生长。
OBJECTIVE: To establish a EGFR-resistant (EGF) -free EGFR wild-type xenograft model and study its possible mechanism of drug resistance. Methods Female BALB / c nude mice were injected subcutaneously with A431 cells. The tumors grew to 150 × 200mm ~ 3 and were given gefitinib 50mg / kg orally once daily for 25 weeks. More sensitive and resistant transplanted tumor genome-wide gene expression profile to find the target gene. The drug-resistant model was treated with blank control group, gefitinib, target gene inhibitor (AMG706), or a mixture thereof for 21 days respectively to detect tumor tissue growth, apoptosis, gene of interest and related cytokine expression. Results C-kit was overexpressed in gefitinib-resistant A431 xenografts, and double-blocking of EGFR and c-Kit signaling synergized to cause apoptosis. Conclusion Gefitinib resistance induced in xenograft model A431 may be related to overexpression of c-Kit. The combination of EGFRIs and c-Kit inhibitors may block this resistance mechanism and inhibit tumor cell growth.