Study About Inhibitory Effect And Its Mechanism Of BD0801 On Hepatocellular Carcinoma Transplanted Tumor In Nude Mice

Objective:To explore the inhibitory effect and its mechanism of BD0801 on human hepatocellular carcinoma transplanted tumor in nude mice.Methods:Human hepatocellular carcinoma cell line SMMC-7721 was cultured in vitro. The xenograft models were established successfully. Forty-two mice which had good homogeneity were divided into seven groups:Group A(BD08012.5mg/kg)、 Group B(BD0801 5mg/kg)、Group C(BD0801 10mg/kg)、Group D(Bev 2.5mg/kg)、 Group E(Bev 5mg/kg)、Group F(Bev 10mg/kg)、G(NS). Identify and compare the best dose of BD0801 and Bev resistance of HCC angiogenesis. Then established fifty-four mice and divided into nine groups:A (BD0801+OXA)、B (BD0801+5-FU)、C (BD0801)、D (Bev+OXA)、E (Bev+5-FU)、F(Bev)、G(OXA)、H (5-FU)、 I (NS).All groups were treated by intraperitoneal injection twice a week. During the three-week therapy period, the general situation, the mice weight and the subcutaneous xenograft size were monitored. After treatment, all nude mice were killed, then all the subcutaneous tranplanted tumor were stripped and measured by calipers and scales. Inhibitory rate of tumor weight and tumor volume were calculated. Tissue H-E staining and transmission electron microscopy detection were used to detect the tumor cell apoptosis. Western-Blots were used to detect the expression of VEGF、Flt-1、KDR.Results:1. Compared with the negative control group, both the moderate and high dose groups of either BD0801 or Bev had a significantly higher inhibitory effect on implanted tumor. Furthermore the moderate and high dose BD0801 groups clearly show stronger tumour inhibitory effect than those of the Bev groups. In contrast with the negative control group, the moderate and high dose groups of both BD0801 and Bev achieved a significant decrease in MVD count on the implanted tumor and the decrease in MVD count seen for BD0801 groups was significantly greater than those of the Bev groups. Western blot test result shows that BD0801 can with greater effect suppress implanted tumor cells through VEGF/VEGFR pathway.2. Compared with monotherapy groups, combination therapy has a significantly enhanced inhibitory effect on the proliferation of implanted tumor. BD0801+5-FU/OXA has a greater inhibitory effect than Bev +5-FU/OXA on the proliferation of implanted tumor. The MVD count of the combination therapy groups is significantly less than the monotherapy groups with that of BD0801 combined 5-FU/OXA significantly lower than the MVD count of Bev combined 5-FU/OXA group. Western blot test results show that BD0801+5-FU/OXA can through the VEGF/VEGFR pathway have a significantly greater inhibitory effect than Bev+ 5-FU/OXA on the proliferation of implanted tumour cells.Conclusion:BD0801 could more effectively inhibit SMMC-7721 transplanted tumor growth on than Bev,with the mechanism related to inhibit cancer cell activity of VEGF/VEGFR pathway. BD0801 combined 5-FU or OXA in vivo can significantly inhibit the growth of SMMC-7721 transplanted tumor,, and its mechanism may be related to enhanced inhibition of VEGF/VEGFR pathway activity on tumor cells.