中国临床药学杂志

目的比较去甲斑蝥素(NCTD)最大耐受剂量化疗(MTD)和低剂量节拍式化疗(LDM)对荷人源肝癌裸鼠肿瘤的生长抑制作用,评价其不良反应,并探讨不同给药方案对血管内皮生长因子(VEGF)蛋白和CD44蛋白表达水平的影响。方法采用人肝癌细胞株建立荷人肝癌裸鼠皮下移植瘤模型。将裸鼠随机分为3组:对照组、NCTD-MTD组、NCTD-LDM组。给药期间测量裸鼠肿瘤体积大小,并观察裸鼠生存情况。处死后计算抑瘤率并检测血清中丙氨酸氨基转移酶(ALT)和肌酐浓度。免疫组化法检测移植瘤组织中VEGF和CD44蛋白表达水平。结果从给药后第9天开始,NCTD-LDM组对肿瘤体积增长的抑制作用明显优于其他2组(P<0.05);给药结束后,对照组、NCTD-MTD组和NCTD-LDM组的瘤质量分别为(0.78±0.22)、(0.73±0.21)和(0.48±0.20)g,NCTD-MTD组和NCTD-LDM组的肿瘤抑制率分别为5.58%和42.83%,NCTD-LDM组相对其他2组的瘤质量差异有统计学意义(P<0.05)。免疫组化结果显示,NCTD-LDM组的VEGF蛋白和CD44蛋白的表达明显低于其他2组;生化结果显示,NCTD-MTD组裸鼠的ALT值和血清肌酐值明显高于对照组和NCTD-LDM组(P<0.05),而NCTD-LDM组并未见明显升高。结论在总给药剂量相同的情况下,NCTD-LDM化疗可显示出更优的肿瘤抑制效果,并对肝肾功能的影响较小,其抗肿瘤机制可能是通过对肿瘤血管和肿瘤细胞转移的抑制作用来提高化疗效果。因此,LDM化疗有望成为提高抗肿瘤效果和降低不良反应的一种理想模式。

AIM To compare the inhibitory effect on nude mice beared human hepatocellular carcinoma by norcantharidin( NCTD) using maximum tolerated dose chemotherapy( MTD) or low dose metronomic chemotherapy( LDM),and to investigate the effect of different dosage regimen on expression levels of vascular endothelial growth factor( VEGF) and CD44 protein. METHODS Human liver cell line was used to establish the mice transplantation tumor model which beared human hepatocellular carcinoma. The nude mice were randomly divided into 3groups: control group,NCTD-MTD group and NCTD-LDM group. Tumor size of nude mice was measured during dosing,and survival condition was also observed. Inhibitory rate was calculated and serum alanine aminotransferase( ALT) and creatinine concentrations were detected after mice sacrificed. Expression level of VEGF and CD44 protein in transplanted tumor tissue was detected by immunohistochemical method. RESULTS From the 9th day after treatment,the inhibition on growth of tumor volume of NCTD-LDM group was obviously better than the other 2groups( P < 0. 05); when the treatment was finished,the tumor weights of control group,the NCTD-MTD and NCTD-LDM groups were( 0. 78 ± 0. 22),( 0. 73 ± 0. 21) and( 0. 48 ± 0. 20) g,respectively; the tumor inhibitory rate of NCTD-MTD and NCTD-LDM groups were 5. 58% and 42. 83%,respectively. Compared to the other 2groups,the tumor weight of NCTD-LDM group had significant difference( P < 0. 05). Immunohistochemical results showed that expression of VEGF protein and CD44 protein in NCTD-LDM group were significantly lower than that in the other 2 groups. Biochemical results showed that ALT values and serum creatinine values in NCTD-MTD group was obviously higher than those of control group and NCTD-LDM group( P < 0. 05),while these two indexes in NCTD-LDM group did not rise significantly. CONCLUSION Under the condition of the same total dose of medicine,NCTD-LDM chemotherapy exerts better tumor inhibitory effect,and has less effect on the liver and kidney function. Its antitumor mechanism may be associated with the inhibitory effect on tumor blood vessels and tumor cell transfer,so as to improve the effect of chemotherapy. Therefore,LDM chemotherapy is expected to become an ideal model for improving anti-tumor effect and reducing adverse reactions.