目的 探讨抑制Src激酶对K562及其衍生的imatinib耐药K562/G细胞体外和体内抗肿瘤作用及分子机制.方法 先在体外检测ZD6474直接抑制Src激酶对细胞凋亡的影响;然后建立裸鼠皮下移植瘤模型,利用灌胃给药的方式给予ZD6474,剂量为25～100 mg/(kg*d),连续给药18 d,观察移植瘤生长情况,并用免疫组化方法分析肿瘤组织的增殖和Src激酶表达情况.结果 ZD6474在体外呈剂量依赖性直接抑制Src激酶活性;特异性抑制Src可以诱导K562和K562/G细胞凋亡,并上调Bax/Bcl-2的比例,但不影响STAT3的活性.口服给予ZD6474可以显著抑制K562、K562/G裸鼠移植瘤的生长(P<0.05);并抑制肿瘤组织中增殖细胞核抗原和Src激酶的表达.结论 ZD6474直接抑制Src激酶,从而抑制imatinib耐药的K562/G和亲本K562细胞增殖,诱导凋亡,并以剂量依赖方式显著抑制K562、K562/G裸鼠移植瘤生长,其机制与ZD6474显著抑制Src激酶活性有关.%Objective To investigate the effects of Src kinase inhibition on chronic myeloid leukemia ( CML ),and to investigate the mechanism. Methods Direct Src kinase inhibition by ZD6474 was assayed by HTScan(R) Src Kinase Assay Kit for evaluation of its inhibited effects on CML. The in vivo anti - tumor activity was evaluated in K562 and K562/G xenografted nude mice by administration of ZD6474 [ 25 ～ 100 mg( kg · d ), p. o. ]. The expression of PCNA and Src kinase were analyzed hy immunohistochemical analysis. Results ZD6474 directly inhibited Src kinase in vitro in a dose - dependent manner. Src kinase - induced imatinib - resistance and up - regulation of Bcl - 2 was verified with PP2. which was a specific Src kinase inhibitor. Administration of ZD6474 produced dose - dependent inhibition of tumor growth, and down - regulation of PCNA and Src kinase in tumor. Conclusion ZD6474 is effective in inhibiting CML cell proliferation. Src kinase plays pivotal roles in the induction of imatinib - resistance, thus producing specific target for treatment of imatinib - resistant CML.
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