An armed oncolytic herpes simplex virus expressing thrombospondin‐1 has an enhanced in vivo antitumor effect against human gastric cancer

Abstract

Advanced gastric cancer is a common disease, but the conventional treatments are unsatisfactory because of the high recurrence rate. One of the promising new therapies is oncolytic virotherapy, using oncolytic herpes simplex viruses (HSVs). Thrombospondin-1 (TSP-1) suppresses tumor progression via multiple mechanisms including antiangiogenesis. Our approach to enhance the effects of oncolytic HSVs is to generate an armed oncolytic HSV that combines the direct viral oncolysis with TSP-1-mediated function for gastric cancer treatment. Using the bacterial artificial chromosome (BAC) system, a 3rd generation oncolytic HSV (T-TSP-1) expressing human TSP-1 was constructed for human gastric cancer treatment. The enhanced efficacy of T-TSP-1 was determined in both human gastric cancer cell lines in vitro and subcutaneous tumor xenografts of human gastric cancer cells in vivo. In addition, we examined the apoptotic effect of T-TSP-1 in vitro, and the antiangiogenic effect of T-TSP-1 in vivo compared with a non-armed 3rd generation oncolytic HSV, T-01. No apparent apoptotic induction by T-TSP-1 was observed for human gastric cancer cell lines TMK-1 cells but for MKN1 cells in vitro. Arming the viruses with TSP-1 slightly inhibited their replication in some gastric cancer cell lines, but the viral cytotoxicity was not attenuated. In addition, T-TSP-1 exhibited enhanced therapeutic efficacy and inhibition of angiogenesis compared with T-01 in vivo. In this study, we established a novel armed oncolytic HSV, T-TSP-1, which enhanced the antitumor efficacy by providing a combination of direct viral oncolysis with antiangiogenesis. Arming oncolytic HSVs may be a useful therapeutic strategy for gastric cancer therapy.