Abstract 1543: The effect of combination of oncolytic herpes virus hrR3 and Bevacizumab in the treatment of experimental model of human gastric cancer
Authors: Tan Gewen , Kasuya Hideki , Sahin Tevfik T. , Shikano Toshio , Yamada Suguru , Kanzaki Akiyuki , Yamamura Kazuo , Fujii Tsutomu , Sugimoto Hiroyuki , Nomoto Shuji , Nishikawa Yoko , Takeda Shin , Nakao Akimasa 
Published: August 2012

Abstract
Gastric cancer is still one of the leading causes of cancer death worldwide. Even with the modern standard therapy, the prognosis of locally advanced or metastatic cases remains poor. Moreover, 50% of the patients with curative resection will suffer from local recurrence. Therapeutic multimodality with a more specific and effective strategy is urgently needed. Oncolytic herpes viruses are good candidates because of broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor subtype A (VEGFA) which inhibits angiogenesis and therefore tumor growth. Our study evaluated the combination of these two novel strategies in the treatment of experimental model of human gastric cancer. The VEGFA gene and protein expression was measured in various cancer cell line(AZ521, MKN45, Capan-1, Hep3B, PLC/PRF/5, WiDr and SKOV-3)by RT-PCR and western blot. The MTT analysis was performed to evaluate efficiency of combination therapy in vitro. The effect on viral replication was evaluated by PCR and tittering of the virus replicating under various doses of Bevacizumab. The in vivo study consisted of 24 BALB/c nude mice which were injected 106 cells into the right flank region. Control group received no treatment. hrR3 group received 107 pfu virus intratumorally. Bevacizumab group received 5mg/kg Bevacizumab intraperitoneally twice a week. Combination group received both intratumoral hrR3 and intraperitoneally bevacizumab at the same dose. Tumor diameters were measured twice a week. 2 days following the last dose of the treatment tumors were collected. Histopathologically CD31 driven microvascular density was evaluated by immunohistochemistry. Apoptosis was evaluated by apoptag immunoperoxidase staining. Viral replication in tissue was evaluated by α-Galactosidase (LacZ) histochemistry. VEGFA gene and protein expression of MKN45 and SKOV3 cell line were the highest. In the in vivo study, the tumor volume of the combination group was smallest among all groups(P&lt;0.05). hrR3 group had the highest Microvascular density (P&lt;0.05). Combination group had higher angiogenesis when compared to Bevacizumab and control groups. LacZ induction was highest in the combination group when compared to hrR3 group (P&lt;0.05). Oncolytic herpes viruses are promising agents for future cancer therapeutics due to wide host range and tumor selective viral distribution. However, penetration of the oncolytic virus in the tumor remains a obstacle for genetically engineered viruses.Virus-associated agent is needed to enhance the antitumor effect of the oncolytic virus. The results of our study show that Bevacizumab increased the viral distribution in the tumor tissue and therefore potent oncolysis resulted in reduction of the tumor. It can be a ideal virus-associated agent in the antitumor therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1543. doi:1538-7445.AM2012-1543