[Anti-angiogenesis effect of arsenic trioxide plus cinobufacin on human hepatocarcinoma transplantation model nude mice].

ABSTRACT

OBJECTIVE: To study the anti-angiogenesis effect and toxicity of arsenic trioxide (As2O3) plus cinobufacin on transplanted human hepatocarcinoma in nude mice, and the acting mechanism of the treatment was explored as well. METHODS: Human hepatocarcinoma was transplanted in nude mouse, and the modeled mice were divided at random into 4 groups, 8 in each group. They were treated respectively with normal saline (GA), 2.5 mg/kg As2O3 (GB), 5 mL/kg cinobufacin (GC) and 2.5 mg/kg As2O3 + 5 mL/kg cinobufacin (GD), by intraperitoneal injection for 21 days. The anti-tumor effects was evaluated by estimating general condition of nude mice, tumor size, microvessel density(MVD) level. Expressions of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in tumor, in tumor tissue of mice as well as pathology of tumor were detected by immunohistochemistry assay, optical microscope, transmission electron microscope (TEM), respectively. Moreover, blood routine and pathological examinations of liver and kidney were performed. RESULTS: The tumor weight and volume were 0.65 +/- 0.25 g and 0.44 +/- 0.14 cm3 in GB, 0.70 +/- 0.27 g and 0.46 +/- 0.19 cm3 in GC, 0.42 +/- 0.16 g and 0.26 +/- 0.11 cm3 in GD, all significantly lower than those in GA (1.06 +/- 0.25 g and 0.67 +/- 0.17 cm3, P < 0.05). The coefficient of drug interaction (CDI) on tumor weight was 0.97 and that on tumor size was 0.86, all less than 1, showing the synergistic action between the two drugs. Expressions of VEGF and EGFR in tumor as well as the MVD were decreased in GB and GC, and the decreasing of these indices were even more significant in GD. Pathologic examination showed the growth of tumor in GB, GC and GD were all inhibited significantly. No obvious toxicity of the treatments to the hepatic, renal and hematopoietic systems in the nude mice was observed. CONCLUSIONS: As2O3 and cinobufacini showed synergistic action in inhibiting human hepatocarcinoma in nude mice and the angiogenesis in tumor. Combined use of the two had no obvious toxicity to the hepatic, renal and hematopoietic systems.