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Adenovirus-mediated soluble FLT-1 gene therapy for ovarian carcinoma
P J Mahasreshti1, J G Navarro, M Kataram
1The Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
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.
Insights
Adenovirus-mediated gene therapy using soluble fms-like tyrosine kinase receptor (sFLT-1) effectively inhibited ovarian tumor growth in mice. This innovative treatment also significantly increased the survival duration of tumor-bearing mice, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Ovarian carcinoma is a significant health concern with limited effective treatments.
- Angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), plays a crucial role in tumor growth and metastasis.
- Soluble fms-like tyrosine kinase receptor (sFLT-1) is a naturally occurring splice variant of VEGF receptor-1 that inhibits VEGF activity.
Purpose of the Study:
- To investigate the efficacy of adenovirus-mediated soluble fms-like tyrosine kinase receptor (sFLT-1) gene therapy in inhibiting ovarian tumor growth.
- To evaluate the impact of this gene therapy on the survival rates of mice with ovarian carcinoma.
Main Methods:
- Constructed an infectivity-enhanced recombinant adenovirus (AdRGDGFPsFLT-1) expressing sFLT-1 and green fluorescent protein (GFP).
- Validated sFLT-1 function in vitro by assessing inhibition of human umbilical vein endothelial cell proliferation.
- Evaluated therapeutic potential in two murine ovarian carcinoma models: subcutaneous inoculation and intraperitoneal inoculation of SKOV3.ip1 cells.
Main Results:
- Adenovirus-expressed sFLT-1 significantly inhibited endothelial cell proliferation in vitro.
- Subcutaneous ovarian tumors in mice treated with AdRGDGFPsFLT-1 were significantly smaller compared to controls.
- Intraperitoneal administration of AdRGDGFPsFLT-1 led to a significant increase in survival time in mice.
Conclusions:
- Adenovirus-mediated sFLT-1 gene therapy demonstrates significant potential for inhibiting ovarian tumor growth.
- This gene therapy approach can effectively increase survival rates in a murine model of ovarian carcinoma.
- Results support further investigation of sFLT-1 gene therapy as a treatment for ovarian cancer.