An Experimental Study Of Prevention Effect Of The Combination Of TNP-470 And MMC On The Growth And Recurrence And Metastasis Of The Mice Bearing Hepatocellular Carcinoma

Objective: To evaluate whether TNP-470 could enhance the anti-tumor and anti-recurrence and anti-metastasis effect of mitomycin (MMC), and the mechanism of that.Methods: First section: Forty orthotopic transplantation of the KM mice bearing hepatocellular carcinoma were randomized into 4 groups : (1)control (3%ethanol,sc, qod, 7 times) ;(2)TNP-470 (30mg/kg, sc, qod, 7 times) ; (3)MMC(2mg/kg,ip,biw, 4 times); (4)TNP-470 (30mg/kg,sc,qod, 7 times )+MMC (2mg/kg,ip,biw,4 times). Total mice were sacrificed two weeks after administration. Then (1)detect the longest and perpendicular dimension (a, b)of the tumor , the volume of the tumor was calculated according to the formula: v=0.5 ab2 , the pre-treatment and the post-treatment weight of the mice; (2)immunohistochemistry was used to detect ki-67, apoptosis , MVD ;(3)electron microscope was used to detect apoptosis.Second section : the tumor was resected to construct the model of postoperative mice, sixty of which were randomized into 4 groups:(1) control (3%ethanol,sc,qod); (2) TNP-470 (30mg/kg,sc,qod); (3) MMC (2mg/kg,ip,biw,flrst week; then qw); (4)TNP-470 (30mg/kg,sc, qod)+ MMC (2mg/kg,ip,biw,flrst week; then qw). Then detect(1)the survival time; (2)the ratio of recurrence , the longest and perpendicular dimension (a, b) of the recurrent tumor; (3) the pre-treatment and post-treatment abdomen circumference of the mice.Results: First section: (1)the tumor growth of every treatmentgroups was significantly different from the control ,the best is the combination group (P<0.05),there was no significant difference in the weight of the mice among the every pre-treatment groups and the post-treatment groups (P>0.05); (2)there was no significant difference in the PI between the TNP-470 and the control group (P>0.05),but, there was significant difference in the AI and MVD between the TNP-470 and the control group (P<0.05), the AI and PI of the combination group is significantly different from the other groups (P<0.05), the MVD of the combination group is significantly different from the control and MMC group (P<0.05) ; (3) electron microscope indicates that apoptotic endothelial cell and tumor cell could be seen in the TNP-470 group, the more apoptotic endothelial cell and tumor cell could be seen in the combination group .Second section: (1)the survival time of the TNP-470 group and the combination group was significantly different from the other treatment groups(P<0.05); (2)the ratio of recurrence and the volume of the recurrent tumor of the combination group was significantly different from the MMC group(P<0.05); (3)the abdomen circumference of the combination group was significantly different from the other groups (P<0.05).Conclusion: TNP-470 could enhance the anti-tumor effect of mitomycin (MMC), the target of TNP-470 is the endothelial cell, the mechanism of additive effect may induce the apoptosis of the tumor cell by the inhibition of angiogenesis.