Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma


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Abstract

We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR-1, sVEGFR-2 and sVEGFR-3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti-VEGF-antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n= 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus-mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti-VEGF-antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n= 21); combination of AdsVEGFR-1, -2 and -3 (n= 21); combination of AdsVEGFR-1, -2, -3 and paclitaxel (n= 9); bevacizumab (n= 14); paclitaxel (n= 9) and carboplatin (n= 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p= 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p= 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p= 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.

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