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.
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.
Antiangiogenic and antilymphangiogenic gene therapy with soluble vascular endothelial growth factor receptor-2 (VEGFR-2) and soluble VEGFR-3 in combination with chemotherapy is a potential new treatment for ovarian carcinoma. We evaluated the safety, toxicology, and biodistribution of intravenous AdsVEGFR-2 and AdsVEGFR-3 combined with chemotherapy in healthy rats (n=90) before entering a clinical setting. The study groups were: AdLacZ and AdLacZ with chemotherapy as control groups, low dose AdsVEGFR-2 and AdsVEGFR-3, high dose AdsVEGFR-2 and AdsVEGFR-3, combination of low dose AdsVEGFR-2 and AdsVEGFR-3 with chemotherapy, combination of high dose AdsVEGFR-2 and AdVEGFR-3 with chemotherapy, and chemotherapy only. The follow-up time was 4 weeks. Safety and toxicology were assessed by monitoring the clinical status of the animals and by histological, hematological, and clinical chemistry parameters. For the biodistribution studies, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used. Low dose (2×10(10) vp) AdsVEGFR-2 and AdsVEGFR-3 gene therapy was well tolerated, even when gene therapy was combined with chemotherapy. Notably, only transient elevation of liver enzymes and mild regenerative changes were seen in liver after the gene transfer in the groups that received high doses (2×10(11) vp) of AdsVEGFR-2 and AdsVEGFR-3 with or without chemotherapy. No life-threatening adverse effects were noticed in any of the treatment groups. The highest protein concentration of soluble VEGFR-2 (sVEGFR-2) in circulation was seen 1 week after the gene transfer. The combination of chemotherapy to gene therapy seemed to prolong the time of detectable transgene protein at least 1 week in the circulation. The expression of AdsVEGFR-2 and AdsVEGFR-3 transgenes was mainly seen in the liver and spleen as detected by qRT-PCR. According to these results, AdsVEGFR-2 and AdsVEGFR-3 gene therapy combined with chemotherapy is safe and can be brought to clinical testing in ovarian cancer patients.
BackgroundVascular endothelial growth factors (VEGFs) are major regulators of intratumoral angiogenesis in ovarian cancer (OVCA). Overexpression of VEGFs is associated with increased tumor growth and metastatic tendency and VEGF-targeting therapies are thus considered as potential treatments for OVCA. Here, we examined the antiangiogenic and antitumoral effects on OVCA of adeno-associated virus 8 (AAV8)-mediated expression of soluble VEGF receptors (sVEGFRs) sVEGFR2 and sVEGFR3 together with paclitaxel and carboplatin chemotherapy.Materials and methodsImmunodeficient mice were inoculated with human OVCA cell line SKOV-3m. Development of tumors was confirmed with magnetic resonance imaging (MRI) and mice were treated with gene therapy and paclitaxel and carboplatin chemotherapy. The study groups included (I) non-treated control group, (II) blank control vector AAV8-CMV, (III) AAV8-CMV with chemotherapy, (IV) AAV8-sVEGFR2, (V) AAV8-sVEGFR3, (VI) AAV8-sVEGFR2 and AAV8-sVEGFR3, and (VII) AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy. Antiangiogenic and antitumoral effects were evaluated with immunohistochemical stainings and serial MRI.ResultsReduced intratumoral angiogenesis was observed in all antiangiogenic gene therapy groups. The combined use of AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy suppressed ascites fluid formation and tumor growth, thus improving the overall survival of mice. Antitumoral effect was mainly caused by AAV8-sVEGFR2 while the benefits of AAV8-sVEGFR3 and chemotherapy were less prominent.ConclusionCombined use of the AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy reduces intratumoral angiogenesis and tumor growth in OVCA mouse model. Results provide preclinical proof-of-concept for the use of soluble decoy VEGFRs and especially the AAV8-sVEGFR2 in the treatment of OVCA.
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.
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