title: Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma.
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.
authors.affiliation: Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Sopo
authors.forename: Maarit
authors.initials: M
authors.lastname: Anttila
authors.forename: Hanna
authors.initials: H
authors.lastname: Sallinen
authors.forename: Laura
authors.initials: L
authors.lastname: Tuppurainen
authors.forename: Anniina
authors.initials: A
authors.lastname: Laurema
authors.forename: Svetlana
authors.initials: S
authors.lastname: Laidinen
authors.forename: Kirsi
authors.initials: K
authors.lastname: Hamalainen
authors.forename: Pasi
authors.initials: P
authors.lastname: Tuunanen
authors.forename: Jonna K
authors.initials: JK
authors.lastname: Koponen
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Seppo
authors.initials: S
authors.lastname: Heinonen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Yla-Herttuala
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D017239:Paclitaxel