Gene therapy of human bladder cancer with adenovirus-mediated antisense basic fibroblast growth factor

We previously investigated the role of basic fibroblast growth factor (bFGF ) as a mediator of angiogenesis, tumorigenicity, and metastasis of transiti onal cell carcinoma (TCC) of the bladder, In the present study, we determin ed whether adenoviral-mediated antisense bFGF gene transfer therapy (Ad bFG F-AS) would inhibit TCCs growing in the subcutis of nude mice. In vitro, Ad bFGF-AS inhibited endothelial cell proliferation and enhanced apoptosis, T he highly metastatic human TCC cell line 253J-BVR was implanted ectopically in the subcutis of athymic nude mice, and therapy was begun when the tumor s reached a diameter between 5 and 7 mm, Intralesional therapy with Ad bFGF -AS decreased the in vivo expression of bFGF and matrix metalloproteinase t ype 9 mRNA and protein, and reduced microvessel density and enhanced endoth elial cell apoptosis, Tumor growth was significantly inhibited by Ad bFGF-A S (mean, 58 mg) compared with controls [saline (mean, 562 mg), beta -galact osidase adenovirus (mean, 586 mg), and sense bFGF adenoviral therapy (Ad bF GF-S; mean, 3012 mg)], These results suggest that Ad bFGF-AS therapy affect s endothelial cells directly and tumor cells indirectly through down-regula tion of bFGF and matrix metalloproteinase type 9, resulting in endothelial cell apoptosis and significant tumor growth inhibition. Furthermore, these studies confirm that bFGF expression is a valid target for the therapy of b ladder cancer.