3,5-二氯苯基双胍抑制黑色素瘤肺转移的裸鼠体内药效学研究

Suppressive effect of 3,5-dichlorophenylbiguanide on pulmonary metastasis of melanoma in nude mice

目的确认整合素αvβ3新型抑制剂3,5-二氯苯基双胍对人黑色素瘤肺转移的抑制作用。方法应用前期建立的人黑色素瘤裸鼠肺转移模型,观察3,5-二氯苯基双胍的治疗效果。裸鼠尾静脉接种黑色素瘤细胞(第1天)后,于第5、9、13、17和21天给予该药物治疗。50 d实验结束,处死裸鼠并取完整的肺组织,Bouin氏液固定24 h后根据肺表面癌结节的大小和数量给予评分,以此评价肺转移的程度。结果 3,5-二氯苯基双胍6、12 mg/kg和24 mg/kg治疗组的转移分数分别为(55.25±13.60)、(35.13±17.36)和(12.83±11.44),与溶剂对照组(转移分数是82.50±17.72)相比具有明显差异(P<0.05)。阳性对照组的转移分数为(11.50±10.44)(P<0.05 vs溶剂对照组),阴性对照组和PBS对照组的转移分数分别为(88.50±17.21)、和(88.87±11.29)(P>0.05 vs溶剂对照组)。结论 3,5-二氯苯基双胍在裸鼠体内能够明显抑制黑色素瘤肺转移,并呈现一定的剂量依赖性。

Objective To observe the suppressive effect of 3,5-dichlorophenylbiguanide on pulmonary metastasis of melanoma in vivo.Methods Human melanoma cell line M21 cells were injected into the tail vein of nude mice（defined as day 1）.The treatment procedure was carried out at days 5,9,13,17,and 21 by tail vein injection of 3,5-dichlorophenylbiguanide at a dose of 6 mg/kg,12 mg/kg or 24mg/kg to the nude mice of the experimental groups.In addition,positive control,negative control,and vehicle control groups were set up.The mice were sacrificed at day 50.The lungs were removed and fixed in Bouin’s fixative solution for 24 h.Metastasis scores were figured out by a formula according to the diameters and numbers of white metastatic nodules on the lung surface.Results The 3,5-dichlorophenylbiguanide treatment reduced the metastasis scores to 55.25±13.60（6 mg/kg）,35.13±17.36（12 mg/kg） and 12.83±11.44（24 mg/kg）,significantly lower than that of the vehicle control group（P〈0.05）.The cRGDfV treatment reduced metastasis score to 11.50±10.44,significantly lower than that of the vehicle control group（P〈0.05）.The metastasis score of the negative control IH1066 treatment group was 88.50±17.21,and that of the untreated group was 88.88±11.29,both with a non-significant difference compared with that of the vehicle control group（82.50±17.72）（P〉0.05）.Conclusion 3,5-dichlorophenylbiguanide shows a suppressive effect on the pulmonary metastasis of melanoma in mice in a dose-dependent manner.