298. Combination Effect of Telomerase-Specific Replication-Competent Adenovirus (Telomelysin, OBP-301) and p53 Gene Therapy in Human Non- Small Cell Lung and Colon Cancer Cells

Abstract

Gene therapy was investigated as a promising treatment for cancer. However, low transduction efficiency limits the efficacy of gene therapy in clinics. We previously demonstrated that telomerase- specific replication-competent adenovirus (Telomelysin, OBP-301), in which the human telomerase reverse transcriptase (hTERT) promotor element drives expression of E1A and E1B genes linked with an IRES, induced selective E1 expression and efficient antitumor effect in human cancer cells, but not normal human fibroblasts. In this study, we evaluated the anticancer effect of the combination therapy of E1-deleted replication-deficient adenovirus expressing the wild-type p53 tumor suppressor gene (ADVEXIN, Ad-p53) and OBP-301 in human H1299 non-small cell lung cancer cells and SW620 colon cancer cells by using cell proliferation assay, immunoblotting, and cell-cycle analysis. We found that E1-deficient Ad-p53 could replicate in human cancer cells in the presence of OBP-301 and kill infected cells more efficiently than Ad-p53 alone or OBP-301 alone. Western Blotting Analysis demonstrated that OBP-301 plus Ad-p53 induced high levels of p53 protein expression, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). In addition, flowcytometry showed that the sub-G1 population was dramatically increased with OBP-301 and Ad-p53 infection. The in vivo combination effect of intratumoral injection of Ad-p53 and OBP-301 in a human tumor xenograft model will be also reported. Our data demonstrate that OBP-301 in combination with Ad-p53 efficiently enhances antitumor activity, and provide the potential to affect the development of oncolytic virotherapy and gene therapy.