埃罗替尼和塞来昔布抑制胆管癌生长和血管生成

Combination of erlotinib with celecoxib inhibits tumor growth and angiogenesis of cholangiocarcinoma

目的:观察表皮生长因子受体(EGFR)酪氨酸激酶抑制剂埃罗替尼与环氧合酶(COX-2)抑制剂塞来昔布对胆管癌荷瘤裸鼠的肿瘤生长协同抑制作用。方法:联合EGFR酪氨酸激酶抑制剂(EGFR-selective tyrosine kinaseinhibitor,EGFR TKI)埃罗替尼和COX-2抑制剂塞来昔布作用于胆管癌细胞株QBC939荷瘤裸鼠,评价药物体内作用效果。结果:埃罗替尼、塞来昔布联合用药显著抑制肿瘤生长,与对照组、埃罗替尼、塞来昔布单药组相比,均有显著性差异。抑制肿瘤生长的作用伴随EGFR下游活性蛋白p-MAPK的下调和VEGF、Ki-67表达的降低。肿瘤组织微血管密度降低。结论:埃罗替尼、塞来昔布抑制胆管癌荷瘤生长,抑制肿瘤细胞增殖,同时抑制肿瘤新生血管。两者具协同作用。靶向抑制EGFR和COX-2通路可以作为胆管癌的潜在治疗方法。

Objective Aberrant activation of the epidermal growth factor receptor and COX-2 is frequently observed in cholangiocarcinoma.This study aims to evaluate the inhibitory effect on the growth of cholangiocarcinoma by simultaneously blocking both EGFR and COX-2.Methods A combination of EGFR-selective tyrosine kinase inhibitor（EGFR TKI） erlotinib with a COX-2 inhibitor（COX-2I） celecoxib was studied for its effects on the growth of transplanted human cholangiocarcinoma in nude mice.Results Tumor growth was significantly inhibited by combined treatment compared with the control（P〈0.01）,celecoxib（P〈0.01）,or erlotinib（P〈0.05） treatment.The synergistic effect of these two agents in combination was also associated with down-regulation of p-MAPK and reduction of vascular endothelial growth factor and Ki-67 expression.Apoptosis was also increased as indicated.Conclusions The combined treatment can inhibit tumor progression in vivo cooperatively by both antiangiogenic effect and direct effects on tumor cell proliferation and apoptosis.This combination regimen may provide a promising strategy for cancer therapy.