Experimental Study Of 3-Bromopyruvate Combined With Trans-arterial Embolization In A Rabbit VX2 Liver Tumor Model

Objective:To explore the safety and efficacy of 3-Bromopyruvate(3-BrPA)combined with trans-arterial embolization for the treatment of rabbit hepatic VX2 carcinoma.Material and method:The hepatic VX2 carcinoma model in rabbit was established the method of direct injection of VX2 tissue suspension to the rabbit liver under the guidance of computed tomography(CT).Success of model establishment was confirmed by enhanced CT scan 2 weeks after.Then the rabbits were randomly divided into 4 groups:A(control group:trans-arterial infusion of 25mL phosphate buffered saline of 10mM);B(infusion group:trans-arterial infusion of 25mL 3-BrPA solution of 1.75 mM);C(embolization group:trans-arterial embolization with 100-300?m Embosphere microsphere);D(combined group:trans-arterial infusion of 25mL 3-BrPA solution of 1.75 mM followed by trans-arterial embolization with 100-300?m Embosphere microsphere).Each rabbit would receive blood test for alanine aminotransferase(ALT)and aspartate aminotransferase(AST)before treatment and in 1,3,7 days after treatment,respectively.Post treatment enhanced CT scan was performed in the 7th day to evaluate the tumor response.Finally,all rabbits were sacrificed,and tumor sample were obtained for hematoxylin-eosin staining(HE)observation and TUNEL test.Results:Success rate of building hepatic VX2 carcinoma model reached 90.3%(28/31).There were 26 rabbits underwent the whole procedure,with the rate for technical success of 92.9%(26/28).Two rabbits died after the intervention,leaving a survival rate of 92.3%(24/26).Rabbits in C and D groups suffered different levels of nausea,vomiting and lethargy in the first three days after embolization,but had restored to normal from the 4th day.The change of liver function between four time points in group A and group B rabbits showed no significant difference(ALT:P=0.441(A),P=0.204(B),AST:P=0.978(A),P=0.801(B)),and the difference between the two groups was not statistically significant(ALT:P=0.999,AST:P=0.998).Meanwhile,the values of ALT and AST in group C and D increased initially and then went down to normal level,which was statistically meaningful(ALT,AST:P=0.001(C,D)).But the difference of variation trend between the two groups was not statistically significant(ALT:P=0.981,AST:P=0.266).The comparative results of tumor response evaluated by enhanced CT scan before and after treatment showed significant difference.Complete response was observed in 2 rabbits in group C(33.3%),and 5 rabbits in group D(83.3%).In the general pathologic inspection,tumor viability was identical in four groups.And the tumor treated with combined therapy was almost destroyed.The necrosis rate determined by TUNEL test showed:26.5%±5.0%in group A;52.0%±5.3%in group B;77.6%±3.7%in group C;89.7%±4.6%in group D.The difference between four groups was statistically significant(F=214.3,p<0.001).Further,the post-hoc analysis revealed that necrosis rate in group B was significantly higher than in group A,which indicated the efficacy of 3-BrPA in suppressing tumor growth;and necrosis rate in group D was significantly higher than either in group B or in group C,which indicated that the efficacy of combined therapy in suppressing tumor growth was stronger than either trans-arterial infusion of 3-BrPA alone or trans-arterial embolization alone.Conclusions:Intra-arterial administration of 3-BrPA was effective in suppressing the growth of VX2 carcinoma in rabbit liver model.And 3-BrPA combined with trans-arterial embolization revealed significantly better efficacy than either trans-arterial infusion of 3-BrPA or trans-arterial embolization alone.3-BrPA treatment would cause no influence to liver function,and it would not reinforce the damage to liver function caused by trans-arterial embolization.Our preliminary results show,it is safe and effective to use 3-BrPA combined with trans-arterial embolization for the treatment of liver cancer in the rabbit hepatic VX2 model.