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Oncolytic virotherapy is emerging as an important modality in cancer treatment. In a previous study, we designed and constructed Ad-Apoptin-hTERTp-E1a (Ad-VT), a dual cancer-selective anti-tumor recombinant adenovirus.To explore the therapeutic effect of recombinant adenovirus Ad-VT together with Etoposide on small cell lung cancer, the ability of Ad-VT alone, Etoposide alone, and a combination of Ad-VT + Etoposide to inhibit proliferation of NCI-H446 and BEAS-2B cells was investigated using the WST-1 method. According to the inhibitory action of different combinations, a combination index (CI) was estimated by CalcuSyn software to select the best combination. The inhibitory effect of Ad-VT combined with Etoposide on NCI-H446 and BEAS-2B cells was detected by crystal violet staining and the CFST method. Hoechst, Annexin V and JC-1 staining were used to explore the inhibitory pathway of Ad-VT combined with Etoposide on NCI-H446 cells. The migratory and invasive abilities of treated NCI-H446 cells were assessed by Transwell and BioCat methods. Tumor volume, body weight and survival rate were measured to analyze the anti-tumor and toxic effects of different treatments in tumor-bearing mice.Ad-VT (20 MOI) combined with Etoposide (400 nM) significantly inhibited NCI-H446 cell proliferation with reduced toxicity of Etoposide to normal cells. Ad-VT induced apoptosis of NCI-H446 cells mainly through the mitochondrial apoptosis pathway, an effect significantly increased by the combined treatment. Ad-VT together with Etoposide significantly inhibited migration and invasion of NCI-H446 cells, inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice.The above results indicate that when combined with Etoposide, Ad-VT may have an important role in synergistically inhibiting tumors.