Specific Inhibitor of Matrix Metalloproteinase Decreases Tumor Invasiveness After Radiofrequency Ablation in Liver Tumor Animal Model.

Objective: To determine whether the specific inhibitor of matrix metalloproteinase (MMP)-batimastat (BB-94)-could decrease the progression of liver tumor after radiofrequency ablation (RFA) and achieve better therapeutic efficacy in an animal model.

Methods: experiments, the proliferation of H22 liver tumor cells was detected by CCK 8 assay and cell migration was detected by Transwell method. experiments, H22 murine liver tumors were used. First, 32 mice with one tumor were randomized into four groups (n = 8 each group): control (PBS only), RFA alone (65°C, 5 min), BB-94 (30 mg/kg), RFA+BB-94. The growth rate of the residual tumor and the end point survival were calculated and the pathologic changes were evaluated. Secondly, a total of 48 tumors in 24 animals (paired tumors) were randomized into three groups (n = 8 each group): control, RFA alone, RFA+BB-94. Each mouse was implanted with two tumors subcutaneously, one tumor was treated by RFA and the other was evaluated for distant metastasis after applying BB-94.

Results: , the proliferation assay demonstrated higher proliferation ability after heat treatment (0.82 ± 0.07 1.27 ± 0.08, P = 0.008), and it could be inhibited by BB-94 (1.27 ± 0.08 0.67 ± 0.06, P = 0.001). In the cell migration assay, the H22 cells demonstrated enhanced tumor invasiveness in the heat group than the control group (33.7 ± 2.1 19.7 ± 4.9, P = 0.011). And it could be significantly suppressed after BB-94 incubation (33.7 ± 2.1 23.0 ± 4.6, P = 0.009). With one tumor animal, the growth rate of the residual tumor in the BB-94+RFA group was slower than that in the RFA alone group (P = 0.003). And combination of BB-94 could significantly prolong the survival of the mice (40.3 ± 1.4d 47.1 ± 1.3d, P = 0.002). The expression of CD31 and VEGF at the coagulation margin were decreased after combined with BB-94. With two tumors animal, the growth of metastasis tumor in the BB-94+RFA group was slower than that in the RFA group (P < 0.001).

Conclusion: BB-94 combined with RFA reduced the invasiveness of the liver tumor and improved the end-point survival. Our data suggested that targeting the MMP process with the specific inhibition could help to increase overall ablation efficacy.