Adenovirus-mediated soluble FLT-1 gene therapy for ovarian carcinoma.

Abstract

PURPOSE: We hypothesized that adenovirus-mediated soluble fms-like tyrosine kinase receptor (sFLT-1) gene therapy can inhibit the ovarian tumor growth and increase survival of mice in the context of ovarian carcinoma. EXPERIMENTAL DESIGN: We constructed an infectivity-enhanced recombinant adenovirus (AdRGDGFPsFLT-1) expressing soluble FLT-1 and green fluorescent protein (GFP). An adenovirus AdRGDGFP expressing GFP alone was used as control. The functional validation of adenovirus-mediated sFLT-1 was determined by an in vitro human umbilical vein endothelial cell proliferation inhibition assay. To evaluate the therapeutic potential of adenovirus-expressed sFLT-1 to inhibit the growth of ovarian tumors and to increase the survival duration of mice with ovarian tumors, two tumor models were used. First, SKOV3.ip1 ovarian carcinoma cells were infected ex vivo with either AdRGDGFPsFLT-1 or AdRGDGFP or uninfected and then inoculated s.c. into BALB/c nude mice, and tumor growth was monitored. Second, SKOV3.ip1 cells were inoculated i.p. into CB17 SCID mice and then treated with two doses of either AdRGDGFPsFLT-1 or AdRGDGFP or with PBS on days 1 and 14 after inoculation of cells, and the survival duration was monitored. RESULTS: Treatment with adenovirus-expressed sFLT-1 significantly inhibited the proliferation of human umbilical vein endothelial cells. The s.c. tumor nodules in mice derived from cells infected with AdRGDGFPsFLT-1 were significantly smaller than those infected with either AdRGDGFP or uninfected. In addition, i.p. administration of the AdRGDGFPsFLT-1 resulted in a significant increase in the survival times of mice compared with AdRGDGFP- or PBS-treated mice. CONCLUSIONS: Our results suggest that adenovirus-mediated sFLT-1 gene therapy can effectively inhibit ovarian tumor growth and increase survival in a murine model of ovarian carcinoma.