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Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor‐specific replicating oncolytic adenovirus  OBP ‐301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid ( ZOL ) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with  OBP ‐301 and  ZOL  against osteosarcomas with bone destruction. The antitumor activity of  OBP ‐301 and  ZOL  in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B,  MNNG / HOS , Sa OS ‐2). The cytotoxic effect of  OBP ‐301 and/or  ZOL  was measured by assay of cell apoptosis. The effect of  OBP ‐301 and  ZOL  on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model.  OBP ‐301 and  ZOL  decreased the viability of human osteosarcoma cells. Combination therapy with  OBP ‐301 and  ZOL  displayed a synergistic antitumor effect, in which  OBP ‐301 promoted apoptosis through suppression of anti‐apoptotic myeloid cell leukemia 1 ( MCL 1). Combination therapy significantly inhibited tumor‐mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of  OBP ‐301 and  ZOL  suppresses osteosarcoma progression via suppression of  MCL 1 and osteoclast activation.

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction