Functional MRI Measurements to Predict Early Adenoviral Gene Therapy Response in Ovarian Cancer Mouse Model

Abstract

Anti-angiogenic and anti-lymphangiogenic gene therapy is a new potential method for the treatment of epithelial ovarian carcinoma. We studied the usefulness and feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) and relaxation measurements as surrogate markers of AdsVEGFR-2, AdsVEGFR-3, AdsNRP-1 and AdsNRP-2 gene therapy treatment responses in an intraperitoneal ovarian cancer mouse model (n= 40). Gene therapy was also combined with paclitaxel and carboplatin chemotherapy. Gene therapy was performed when visible tumors were noticed in MRI. Adenoviral gene transfer was dosed intravenously (2×10 9 pfu), while chemotherapy was dosed intraperitoneally. The study groups were: AdLacZ as controls (group I); AdsVEGFR-2 and AdsVEGFR-3 (group II); combination of AdsVEGFR-2, AdsVEGFR-3 and chemotherapy (group III) and AdsNRP-1 and AdsNRP-2 (group IV). Antitumor effectiveness was assessed by sequential MRI, immunohistochemistry, microvessel density, overall tumor growth, formation of ascites and survival time. Early responses in tumor tissue were evaluated with MRI measurements using relaxation times T 2 , T 1ρ , T RAFF2 , T RAFF4 and water apparent diffusion coefficient (ADC). The mean survival of mice (30 days) was significantly prolonged in group II as compared to controls (24 days) or other treatment groups (p= 0.003). Microvessel density (MVD) and total vascular area (TVA) were significantly lower compared to controls in all groups: group II (p= 0.001), group III (p= 0.002), group IV (p= 0.026). T 2 relaxation times were significantly increased at day 8 after the gene transfer in the combination gene therapy and chemotherapy group III compared to controls (p= 0.005). ADC values in the tumors were significantly increased in group IV at four days compared to controls (p= 0.044). Early changes in T 2 relaxation times and ADC values after gene therapy suggest the potential of T 2 relaxation time measurements and DW-MRI as early markers of treatment response after anti-angiogenic gene therapy and chemotherapy.