三七总皂苷联合环磷酰胺节律化疗抗肿瘤效应观察

Anti-tumor effect of panax notoginsenosides combined with cyclophosphamide metronomic chemotherapy

目的研究三七总皂苷(panax notoginsenosides,PNS)联合低剂量环磷酰胺(CTX)节律化疗的抑瘤、抗血管生成及对免疫功能的调节作用。方法小鼠爪垫皮下注射B16细胞,建立B16-BL6黑色素瘤自发性转移模型。分为模型组、大剂量CTX组(MTD组)、低剂量CTX组(节律组)、三七总皂苷组、三七总皂苷联合低剂量CTX组(联合组)。观察抑瘤率、胸腺和脾脏的脏器指数;ELISA法测定IL-2含量;进行外周血白细胞计数;肿瘤微血管密度(MVD)、血管内皮生长因子(VEGF)和趋化因子受体4(CXCR4)的表达情况;计数肺转移结节数。结果节律组、三七总皂苷组及联合组小鼠肿瘤生长缓慢,抑瘤效果持久而稳定。联合组抑瘤率66.15%(P<0.01),对瘤体有较好的抑制作用。节律组相对于大剂量CTX组毒副反应降低,与PNS伍用后免疫功能各项指标明显提升,与MTD组比较有显著性差异(P<0.01),接近模型组水平,MVD、VEGF及CRCX4表达均下降(P<0.05),能够有效减少肺转移瘤灶数量。结论三七总皂苷与低剂量CTX联合应用显示出有效地抗血管生成协同作用,减少转移,抑瘤效果持久,毒副反应小,能够提高小鼠整体机能状态与免疫水平。

Objective To observe the anti-tumor effect, anti-angiogenic effect and immune regulation of panax notoginsenosides （ PNS ） combined with low-dose cyclophosphamide （ CTX ） metronomic chemotherapy. Methods The model of B16-BL6 melanoma spontaneous metastasis was established by hypodermic injection of B16 cells in the palmula in mice. All mice were randomly divided into the model group, high-dose CTX group （MTD group）, low-dose CTX group （metronomic group）, PNS group and PNS combined with low-dose CTX group （combined group）. The tumor-inhibition rate and organ indexes of thymus and spleen were observed. The content of interleukin-2 （IL-2） was determined by ELISA, peripheral blood WBC was counted, and the tumor microvessel density （MVD） and the expressions of vascular endothelial growth factor （VEGF） and chemokine receptor-4 （CXCR-4） were detected by applying immunohistochemical staining. The nodules of lung metastasis were counted. Results In the metronomic group, PNS group and combined group the tumor grew slowly and the tumor-inhibition effect was permanent and stable. The tumor-inhibition rate was 66. 15% in the combined group with a better tumor-inhibition effect （P 〈0.01 ）. The toxicity and side effects were decreased in the metronomic group compared with those in the MTD group. The all indexes of immunity were improved in the combined group with a significant difference （P 〈0.01 ） compared with those in the MTD group and reached the level in the model group. MVD and the expressions of VEGF and CRCX4 were decreased （P 〈0.05）, and the nodules of lung metastasis were reduced in the combined group. Conclusion PNS combined with low-dose CTX shows a synergistic anti-angiogenic effect, inhibits tumor metastasis with a permanent tumor-inhibition effect and lower toxicity and side effects, and improves the whole body function and immune level.