Laura Tuppurainen1, Hanna Sallinen, Anni Karvonen, Elina Valkonen, Hanne Laakso, Timo Liimatainen, Elisa Hytönen, Kirsi Hämäläinen, Veli-Matti Kosma, Maarit Anttila, Seppo Ylä-Herttuala. 1. *Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, and †Institute of Clinical Medicine, Gynecology, and Pathology and Forensic Medicine, University of Eastern Finland; ‡Department of Gynecology, Kuopio University Hospital; §NMR Research Group, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland; ∥Department of Pathology and ¶Gene Therapy Unit, Kuopio University Hospital; and #Science Service Center, Kuopio University Hospital, Kuopio, Finland.
Abstract
OBJECTIVES: Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer. METHODS: An intraperitoneal human ovarian cancer xenograft model in nude mice (n = 44) was used in this study. Gene therapy was given intravenously when the presence of sizable tumors was confirmed in magnetic resonance imaging. The study groups were as follows: AdCMV as a control (group I), AdCMV with chemotherapy (group II), AdsVEGFR2 and AdsTie2 (group III), and AdsVEGFR2 and AdsTie2 with chemotherapy (group IV). Antitumor effectiveness was assessed by overall tumor growth, ascites, immunohistochemistry, microvessel density, and sequential magnetic resonance imaging analyses. RESULTS: AdsVEGFR2 and AdsTie2 gene therapy (group III) significantly reduced tumor weights as compared with group II (P = 0.007). Accumulation of ascites was significantly reduced when the mice were treated with AdsVEGFR2 and AdsTie2 gene therapy or with combined gene therapy and chemotherapy as compared with controls (P = 0.029 and P = 0.010, respectively). Vascular endothelial growth factor and Ang2 levels in ascites fluid were elevated after the gene therapy. CONCLUSIONS: Combined inhibition of VEGF/VEGFR2 and Ang/Tie2 pathways provided efficient therapy for ovarian cancer in mice. In addition, antiangiogenic gene therapy has potential as a treatment for the accumulation of ascites.
OBJECTIVES:Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer. METHODS: An intraperitoneal humanovarian cancer xenograft model in nude mice (n = 44) was used in this study. Gene therapy was given intravenously when the presence of sizable tumors was confirmed in magnetic resonance imaging. The study groups were as follows: AdCMV as a control (group I), AdCMV with chemotherapy (group II), AdsVEGFR2 and AdsTie2 (group III), and AdsVEGFR2 and AdsTie2 with chemotherapy (group IV). Antitumor effectiveness was assessed by overall tumor growth, ascites, immunohistochemistry, microvessel density, and sequential magnetic resonance imaging analyses. RESULTS: AdsVEGFR2 and AdsTie2 gene therapy (group III) significantly reduced tumor weights as compared with group II (P = 0.007). Accumulation of ascites was significantly reduced when the mice were treated with AdsVEGFR2 and AdsTie2 gene therapy or with combined gene therapy and chemotherapy as compared with controls (P = 0.029 and P = 0.010, respectively). Vascular endothelial growth factor and Ang2 levels in ascites fluid were elevated after the gene therapy. CONCLUSIONS: Combined inhibition of VEGF/VEGFR2 and Ang/Tie2 pathways provided efficient therapy for ovarian cancer in mice. In addition, antiangiogenic gene therapy has potential as a treatment for the accumulation of ascites.
Authors: Gregory D Conway; Marguerite S Buzza; Erik W Martin; Nadire Duru; Tierra A Johnson; Raymond J Peroutka; Nisha R Pawar; Toni M Antalis Journal: J Mol Med (Berl) Date: 2019-03-25 Impact factor: 4.599
Authors: Ana Rosa Rama Ballesteros; Rosa Hernández; Gloria Perazzoli; Laura Cabeza; Consolación Melguizo; Celia Vélez; Jose Prados Journal: Cancer Gene Ther Date: 2019-09-24 Impact factor: 5.987