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Combined Gene Therapy Using AdsVEGFR2 and AdsTie2 With Chemotherapy Reduces the Growth of Human Ovarian Cancer and Formation of Ascites in Mice
  1. Laura Tuppurainen, MSc, MB*,
  2. Hanna Sallinen, MD, PhD*,,,
  3. Anni Karvonen, MB*,
  4. Elina Valkonen, BS*,
  5. Hanne Laakso, MSc*,§,
  6. Timo Liimatainen, MD, PhD*,§,
  7. Elisa Hytönen, MD, PhD*,
  8. Kirsi Hämäläinen, MD, PhD,
  9. Veli-Matti Kosma, MD, PhD,
  10. Maarit Anttila, MD, PhD*,, and
  11. Seppo Ylä-Herttuala, MD, PhD, FESC*,,#
  1. *Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, and
  2. Institute of Clinical Medicine, Gynecology, and Pathology and Forensic Medicine, University of Eastern Finland;
  3. Department of Gynecology, Kuopio University Hospital;
  4. §NMR Research Group, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland;
  5. Department of Pathology and
  6. Gene Therapy Unit, Kuopio University Hospital; and
  7. #Science Service Center, Kuopio University Hospital, Kuopio, Finland.
  1. Address correspondence and reprint requests to Seppo Ylä-Herttuala, MD, PhD, FESC, A. I. Virtanen Institute, University of Eastern Finland, PO Box 1627, Kuopio FIN-70211, Finland. E-mail: Seppo.Ylaherttuala@uef.fi.

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.

  • Ascites
  • Gene therapy
  • Ovarian cancer
  • Tie2
  • VEGF

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Footnotes

  • This study was supported by Finnish Academy, Kuopio University Hospital (VTR grant), Ida Montini Foundation, Finnish Cultural Foundation, Instrumentarium Foundation, Cancer Society of North Savo, Foundation for Research on Viral Diseases, Finnish Medical Foundation, and Sigrid Juselius Foundation.

  • The authors declare no conflicts of interest.

  • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

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