Antiangiogenic therapy is a promising strategy for the treatment of cancer since tumor development and metastases require angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most important factors in tumor angiogenesis. In the present study, we investigated the antitumor effect of an adenovirus (AdVEGF-ExR) expressing the extracellular domain of the human VEGF receptor (flt-1) using two different urological tumor/mouse systems. RENCA, a renal cell carcinoma of BALB/c origin, and MBT-2, a poorly differentiated transitional carcinoma of C3H/He origin, were used. Both types of tumor were in vitro infected with AdVEGF-ExR and inoculated subcutaneously into the abdomens of syngenenic mice, and tumor growth was measured twice weekly. In some experiments, BALB/c mice with established RENCA tumors were injected intramuscularly with AdVEGF-ExR as a therapeutic model. The cytotoxicity of spleen cells from the tumor-rejected mice was assessed by 51Cr-release assay. Although the in vitro cell growth of either MBT-2 or RENCA was not affected by infection with AdVEGF-ExR, the in vivo growth of both AdVEGF-ExR-infected tumors was significantly suppressed in the syngeneic mice. In addition, although 2 of 5 mice rejected the AdVEGF-ExR-infected RENCA, tumor-specific cytotoxic T lymphocytes were not generated from their spleen cells, thus suggesting no cellular immune response. In a therapeutic model, intramuscular injections of AdVEGF-ExR at a remote site also significantly suppressed the growth of the subcutaneously established RENCA. These results indicate that the adenovirus-mediated expression of a soluble VEGF receptor can be an effective therapy for urological cancer treatment; however, such VEGF-targeted gene therapy is not necessarily accompanied by subsequent antitumor T cell immunity.

Related Articles