抑制Src酪氨酸激酶对人类肺腺癌小鼠皮下移植瘤的抑制作用及其机制

 【摘要】　目的　探讨抑制Src酪氨酸激酶对人类肺腺癌小鼠皮下移植瘤的影响及其机制。方法　采用雄性严重联合免疫缺陷（SCID）小鼠，建立肺腺癌PC-9和A549细胞诱导的皮下移植瘤动物模型，采用免疫组织化学法研究抑制Src酪氨酸激酶对肺腺癌皮下移植瘤增生指数（PI）（Ki-67染色）和微血管密度（MVD）（CD31染色）的影响。结果　PC-9细胞皮下移植瘤对Src酪氨酸激酶抑制剂非常敏感，治疗组和对照组之间差异有统计学意义（P＜0.01）。10 mg?kg-1?d-1治疗组和50 mg?kg-1?d-1治疗组之间差异也有统计学意义（P＜0.01）。停药1周时10 mg?kg-1?d-1和50 mg?kg-1?d-1治疗组的抑瘤率分别为33.19 %和84.79 %。A549细胞皮下移植瘤对Src酪氨酸激酶抑制剂不敏感。在PC-9细胞皮下移植瘤中，50 mg?kg-1?d-1 Src酪氨酸激酶抑制剂治疗组和对照组相比，PI显著降低 （P＜0.01）。在A549细胞皮下移植瘤中，PI略有下降 （P＞0.05）。在PC-9和A549细胞皮下移植瘤中，50 mg?kg-1?d-1 Src酪氨酸激酶抑制剂治疗组和对照组相比，MVD均显著降低（P＜0.05）。结论　抑制Src酪氨酸激酶通过直接抑制肺腺癌细胞增生和间接抑制血管新生，进而抑制肺腺癌细胞皮下移植瘤生长。

Inhibition of Src tyrosine kinase on subcutaneously transplanted tumor of human lung adencarcinoma hi mice and its mechanism

Objective To study the effect of Src tyrosine kinase inhibition on subcutaneously transplanted tumor of human lung adenocarcinoma in mice and its mechanism. Methods For the subcutaneously transplanted tumor model, A549 cells or PC-9 cells were inoculated into SCID mice by subcutaneous injection. Immunohistochemistry was used to show the effect of Src tyrosine kinase inhibition on proliferation index (Ki-67 staining) and microvessel density (CD31 staining) of subcutaneously transplanted tumor of human lung adenocarcinoma in mice. Results Subcutaneously transplanted tumor of PC-9 cells was sensitive to src tyrosine kinase inhibitor. There was significant difference between treatment group and control group (P <0.01). There was significant difference between the two treatment group too (P <0.01). Stopping treatment for 1 week, the inhibition rate of tumor growth were 33.19 % and 84.79 % in 10 mg·kg-1·d-1 and 50 mg·kg-1·d-1 treatment group, respectively. The same treatment was less effective to subcutaneous tumors produced by A549 cells. Treatment with 50 mg·kg-1·d-1 Src tyrosine kinase inhibitor significantly reduced the proliferation index of subcutaneously transplanted tumor produced by PC-9 cells (P<0.01) and tended to reduce the proliferation index of subcutaneously transplanted tumor produced by A549 cells (P >0.05). Treatment with 50 mg·kg-1·d-1 Src tyrosine kinase inhibitor significantly reduced micro vascular density in both PC-9 and A549 induced subcutaneous tumors (P <0.05). Conclusion Inhibition of Src tyrosine kinase could suppress the progression of subcutaneously transplanted tumor, not only by the inhibition of cell proliferation of lung adenocarcinoma cells directly, but also by the inhibition of angiogenesis indirectly.