重组人血管内皮抑素注射液恩度抑制裸鼠非小细胞肺癌淋巴转移

Inhibitory effect of endostar,a recombinant human endostatin injection,against lymphatic metastasis of non-small cell lung cancer in nude mice

目的探讨重组人血管内皮抑素注射液恩度(endostar)对非小细胞肺癌淋巴转移的抑制作用。方法于裸鼠右侧腋窝经皮下注射A549肺癌细胞(1×107/mL,0.2mL)建立裸鼠荷瘤模型,选择建模成功的56只裸鼠随机分为8组(n=7):对照组(生理盐水0.2mL,1次/d),顺铂组(顺铂20μg,隔日1次),3种浓度恩度组(恩度2、4、6mg/kg,1次/d),3种浓度恩度+顺铂(恩度2、4、6mg/kg,1次/d;顺铂20μg,隔日1次)。所有实验用药均经尾静脉注射,连续给药14d。给药结束后观察7d,测量并记录肿瘤直径,统计各组肿瘤大小的变化。处死裸鼠,对肿瘤组织及可疑转移淋巴结采用H-E染色和免疫组织化学染色,并计算各组淋巴转移阳性率、转移淋巴结数目及微淋巴管密度。结果各用药组给药后与给药前肿瘤直径差值均小于对照组(P<0.05),且3种浓度恩度+顺铂组的肿瘤直径差值均小于3种浓度恩度组和顺铂组(P<0.05)。3种浓度恩度组和3种浓度恩度+顺铂组的淋巴转移阳性率、转移淋巴结数目及微淋巴管密度均低于对照组和顺铂组(P<0.05);6mg/kg恩度组和6mg/kg恩度+顺铂组淋巴转移阳性率、转移淋巴结数目及微淋巴管密度均低于2、4mg/kg恩度组和2、4mg/kg恩度+顺铂组(P<0.05)。结论恩度和顺铂均能抑制非小细胞肺癌肿瘤生长,恩度与顺铂联合使用对肿瘤生长的抑制作用强于两者单独使用;恩度能够抑制肿瘤微淋巴管生成及肿瘤淋巴转移,且作用强度与浓度有关,顺铂未发现类似作用。

Objective To study the inhibitory effect of recombinant human endostatin injection-endostar against lymphatic metastasis of non-small cell lung cancer （NSCLC）. Methods The mouse tumor model was established by subcutaneously injecting 0.2 mL A549 human lung cancer cell suspension （1 × 10^7/mL） in the right armpit of nude mice. Fifty-six tumor- bearing nude mice were randomly divided into eight groups（n= 7）, including control group （physiological saline 0.2 mL, 1/d）, cisplatin group （cisplatin 20 μg, every other day）, three endostar groups （endostar 2, 4, 6 mg/kg：1/d）, and three endostar plus cisplatin groups （adding cisplatin 20 μg to three endostar groups, every other day）. The drugs were injected via the tail vein for 14 d, and the animals were observed for 7 d following the last administration. Tumor diameters were recorded in each group and the changes of tumor size were observed. The tumor tissues and suspicious lymph nodes were subjected to H-E staining and immunohistochemical staining; the staining results were used to calculate the lymphatic metastasis rate, number of metastatic lymph nodes and micro-lymphatic vessel density （MLVD） of each group. Results The pre- and post-treatment differences of tumor diameters in all the experimental groups were significantly smaller than that in the control group, and those of the three endostar plus cisplatin groups were significantly smaller than those of the three endostar groups or cisplatin group （P〈0.05）. The lymphatic metastasis rate, number of metastatic lymph nodes and MLVD in three endostar groups and three endostar plus cisplatin groups were significantly less than that in control group and cisplatin group （P〈 0. 05）. Lymphatic metastasis positive rate, number of metastatic lymph nodes and MLVD in endostar plus cisplatin group were significantly lower or smaller than those in the control group and cisplatin group（P〈0.05） ; for the three endostar groups and the three endostar plus cisplatin groups, the above three parameters in 6 mg/kg endostar group and 6 mg/kg endostar plus cisplatin group were significantly lower or smaller than those in 2 mg/kg and 4 mg/kg endostar groups or 2 mg/kg and 4 mg/kg endorstar plus cisplatin groups （P〈0.05）. Conclusion Both endostar and eisplatin can inhibit tumor growth, and combination of both has a stronger inhibition than they are used alone. Endostar can inhibit tumor lymphangiogenesis and lymphatic metastases in a concentration associated manner, which is not found for eisplatin.