Adenoviral-mediated gene therapy of human bladder cancer with antisense interleukin-8

We previously demonstrated the importance of interleukin-8 (IL-8) as a medi ator of angiogenesis, tumorigenicity, and metastasis of transitional cell c arcinoma (TCC) of the bladder. In the present study, we evaluated the feasi bility of adenoviral mediated antisense IL-8 gene transfer (Ad IL-8-AS) as therapy for established TCC. In vitro, Ad IL-8-AS inhibited endothelial cel l proliferation and enhanced endothelial cell apoptosis. The highly metasta tic human TCC cell line 253J B-V-R was implanted into the subcutis of athym ic nude mice, and intralesional therapy with Ad IL-8-AS commenced when the tumors reached a diameter between 5 and 7 mm. Tumor growth was significantl y inhibited compared with therapy in controls (saline and beta -galactosida se adenovirus). Ad IL-8-AS therapy decreased the in vivo expression of IL-8 and matrix metalloproteinase type 9 (MMP-9), reduced microvessel density, and enhanced endothelial cell apoptosis. These results indicate that Ad IL- 8-AS therapy targets both tumor cells and host endothelial cells resulting in endothelial cell apoptosis and significant inhibition of tumor growth.