Abstract
Background: The high prevalence and poor prognosis of breast cancer provides a strong rationale for developing new treatment strategies. Oncolytic herpes simplex viruses has a promising prospect because of its selectivity, and the replicating and tumor killing ability. In our study, the antitumor effect by combining oncolytic virus HF10 and Bevacizumab in the treatment of human breast cancer xenograft is evaluated. Methods: The VEGFA gene transcription and protein expression were measured in candidate cell lines (MCF-7,T47D and MDA-MB-231) by RT-PCR, Western blot and ELISA. The MTT analysis was applied to evaluate the efficiency of the combination therapy in vitro. Viral replication was assessed by PCR and plaque assay. Animal models were formed by implanting MDA-MB-231 tumor in the flank site of female BALB/c nude mice. The HF10 group of advanced tumor model received two injections of 106 pfu/dose intratumorally on Day 1 and Day 14. The HF10 group of single tumor model received single injection of 106 pfu/dose intratumorally on Day 1. The Bevacizumab group received 5µg/g Bevacizumab intra-peritoneally twice a week for two weeks. The combination group received both intratumoral HF10 and intraperitoneal Bevacizumab at the same dose of single treatment groups. The tumor diameter was measured twice a week. On Day 3 and Day 36, the tumors were collected and observed respectively. Histopathological parameters were HIF1α, VEGFA, CD31 driven microvascular density, Caspase 3 and HSV-1 antigen. Results: MDA-MB-231 cells have the highest level of VEGFA expression, while T47D cells have the lowest level. The cytotoxic effect of HF10 is time- and dose- dependent in vitro. The combination therapy does not affect viral replication in vitro. The combination group has the smallest tumor volume comparing with other groups in both animal models (P<0.05). The combination therapy induces synergistic antitumor effect in both animal models. Viral distribution is significantly enhanced in the combination group compared to the HF10 group on both Day 3 and Day 36. Enhanced tumor hypoxia and the up-regulation of angiogenesis gene as well as enlarged population of apoptotic cells in the combination group are also demonstrated in the tumor sample on Day 3. Conclusions: Increased angiogenesis effect and limited viral distribution remain obstacles of oncolytic viral therapy. Anti-angiogenesis reagent is considered to be effective to achieve better antitumor effect of oncolytic virus. Our results show that Bevacizumab enhances viral distribution as well as tumor hypoxia and enlarges the population of apoptotic cells, and therefore induces a synergistic antitumor effect. It can be a promising virus-associated agent in the anticancer treatment.
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