抑制Src酪氨酸激酶对小鼠肺转移癌的干预作用

摘要

Objective :To study the effect of Src tyrosine kinase inhibition on pulmonary metastasis tumor in mice and its mechanism. Methods: For lung metastasis model, A549 cells were injected into NK cell - depleted SCID mice via the tail vein. Mice were orally given every day with or without Src tyrosine kinase inhibitor to examine the effect of Src tyrosine kinase inhibition on experimental lung metastasis. Immunohistochemistry was used to test the effect of Src tyrosine kinase inhibition on proliferation index ( Ki67 staining ) and microvessel density ( CD31 staining ) of experimental lung metastasis in mice. Results : A549 cells developed numerous small lesions on the surface of the lung in 3 groups , but the nodules of lung in 50mg/kg/d group was smaller than that of control group, representing significantly less lung weight compared to control group and 50mg/kg/d group( P ＜ 0. 05 ). Treatment with lOmg/ kg/d Src tyrosine kinase inhibitor had no significant effect on the lung weight. Treatment with Src tyrosine kinase inhibitor did not cause weight loss of mice significantly, however, inoculated A549 cells 35 days later, the wight in control group was significantly loss( P ＜ 0. 01 ). Treatment with 50mg/kg/d M475271 not only reduced the number and the size of metastatic lesions, but also inhibited the number of Ki67 - positive proliferating tumor cells in lung metastases produced by A549 cells( P ＜ 0. 001 ). Conclusion : Src tyrosine kinase inhibition could suppress the progression of lung metastasis by the inhibition of local cell proliferation and invasion of A549 cells.%目的:探讨抑制Src酪氨酸激酶对小鼠肺转移癌的干预作用及其机制.方法:采用雄性严重联合免疫缺陷(SCID )小鼠,敲除NK细胞,建立肺腺癌A549细胞诱导的实验性肺转移癌动物模型.每天给予小鼠口服Src酪氨酸激酶抑制剂,研究抑制Src酪氨酸激酶对实验性肺转移癌的影响;采用免疫组化法研究抑制Src酪氨酸激酶对转移瘤中增生指数(Ki67染色)和微血管密度(CD31染色)的影响.结果:A549细胞在肺表面形成弥漫性的转移性损伤,50mg/kg/d Src酪氨酸激酶抑制剂口服治疗组肺表面比对照组光滑,肺重量明显小于对照组和10mg/kg/d治疗组(P<0.05),而10mg/kg/d治疗组的肺重量和对照组相比没有明显差别.A549细胞接种后35天,对照组小鼠体重显著下降(P<0.01),而治疗组未见小鼠体重明显下降.口服Src酪氨酸激酶抑制剂 50mg/kg/d,明显减少肺组织内转移性肺损伤的数目和面积,同时显著减少Ki67阳性的增生性肿瘤细胞数(P<0.001).结论:抑制Src酪氨酸激酶通过抑制局部增殖和浸润抑制A549细胞诱导的肺转移癌.