ZD55-TRAIL

Oncolytic adenoviruses (OA) have been investigated as virotherapeutic agents for the treatment of cervical cancer and thus far results are promising. However, the cytotoxicity of the viruses requires improvement. The present study demonstrated that this can be achieved by combining ZD55-TRAIL, an OA containing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene, with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). It was demonstrated that these agents act synergistically to kill HeLa cells by inducing G2 growth arrest and apoptosis. Notably, in a mouse xenograft model, ZD55-TRAIL/SAHA combination inhibited tumor growth. At the molecular level, it was found that upregulation of IκBα and the p50 and p65 subunits of nuclear factor-κB induced by ZD55-TRAIL, can be abrogated by SAHA treatment. These data strongly suggested that ZD55-TRAIL/SAHA co-treatment may serve as an effective therapeutic strategy against cervical cancer.

Replication-competent adenovirus armed with therapeutic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been shown to sensitize cancer cells to chemotherapy and radiotherapy. However, the synergistic antitumor effect of replication-competent adenovirus expressing TRAIL and the cytotoxic chemotherapy in bladder cancer remains to be determined. Bladder cancer T24 cells or mouse tumor xenografts were infected with replication-competent adenovirus armed with human TRAIL (ZD55-TRAIL) alone or in combination with gemcitabine. The mRNA and protein levels of TRAIL were determined by "Reverse transcription polymerase chain reaction" and Western blotting, respectively. Cell viability was tested by CCK8 assay. Tumor growth in the mice was monitored every week by measuring tumor size. Cell apoptosis was detected by Annexin V-FITC staining and TUNEL assay. We found that adenovirus ZD55-TRAIL efficiently replicated both in cultured bladder cancer T24 cells and T24 mouse tumor xenograft as demonstrated by the overexpression of TRAIL and E1A. Gemcitabine did not affect the expression of TRAIL. In cultured T24 cells, ZD55-TRAIL enhanced the growth inhibitory effects of gemcitabine, accompanied by increased apoptosis. Similarly, ZD55-TRAIL synergistically enhanced the antitumor effect and induction of apoptosis following gemcitabine treatment in mouse T24 xenografts. In conclusion, replicative adenovirus armed with TRAIL synergistically potentiates the antitumor effect of gemcitabine in human bladder cancer. Our study provides the basis for the development of ZD55-TRAIL in combination with conventional chemotherapy for the treatment of bladder cancer.