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Antiangiogenic gene therapy in a rat glioma model using a dominant-negative vascular endothelial growth factor
M R Machein1, W Risau, K H Plate
1Department of Neuropathology, Freiburg University Medical School, Germany.
Abstract:
Malignant gliomas are a prominent target for cancer gene therapy approaches because of their poor prognosis despite all currently available therapies. Gene therapy strategies developed to interfere with the normal function of vascular endothelial growth factor receptors have been successfully used in different experimental models to block tumor angiogenesis and to inhibit tumor growth. In this study we examined whether retroviruses encoding a mutant VEGF receptor 2 (VEGFR-2) could suppress tumor angiogenesis and thereby prolong the survival of rats bearing syngeneic intracerebral glioma tumors. Survival time of rats with intracerebral tumors was significantly prolonged in a dose-dependent manner when retroviruses carrying a VEGFR-2 mutant were cotransplanted with tumor cells. No effect on survival was observed in rats that received virus-producing cells or virus supernatant intracerebrally after 5 days of tumor injection. In established subcutaneous tumors treatment with multiple injections of virus-producing cells also inhibited tumor growth in a dose-dependent manner. After implantation of tumor cells stably transfected with a truncated form of VEGFR-2, rats exhibited a rate of survival similar to that of animals treated with high numbers of virus-producing cells encoding the truncated form of VEGFR-2. Morphologically, tumors showed signs of impaired angiogenesis, such as extensive necrosis and reduced tumor vascular density. These results suggest a dual mode of function of truncated VEGFR-2, namely dominant-negative inhibition of VEGFR-2 function and VEGF depletion by receptor binding. We further explored the safety of retrovirus-mediated gene transfer. Although virus sequences were found in different tissues after intracerebral injection of virus-producing cells, no morphological changes were observed in any tissue after a follow-up time of 6 months. Our results indicate that VEGFR-2 inhibition is useful for the treatment of malignant gliomas.
Insights
Gene therapy using a mutant vascular endothelial growth factor receptor 2 (VEGFR-2) extended survival in rats with malignant gliomas. This approach inhibited tumor growth and angiogenesis, offering a promising strategy for glioma treatment.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Malignant gliomas have a poor prognosis despite current therapies.
- Vascular Endothelial Growth Factor Receptor (VEGFR) targeted gene therapy shows promise in blocking tumor angiogenesis and growth.
Purpose of the Study:
- To investigate if retroviruses encoding a mutant VEGFR-2 could suppress tumor angiogenesis and prolong survival in rats with intracerebral glioma tumors.
Main Methods:
- Retroviruses encoding a mutant VEGFR-2 were cotransplanted with glioma cells in rats.
- Tumor growth and survival rates were monitored. Established subcutaneous tumors were treated with virus-producing cells.
- Tumor morphology, including vascular density and necrosis, was assessed.
Main Results:
- Cotransplantation of retroviruses with VEGFR-2 mutant significantly prolonged survival in a dose-dependent manner.
- Established subcutaneous tumors showed inhibited growth with virus-producing cell injections.
- Tumors exhibited impaired angiogenesis, necrosis, and reduced vascular density, suggesting dual VEGFR-2 inhibition and VEGF depletion.
Conclusions:
- Truncated VEGFR-2 demonstrates a dual mode of function: dominant-negative inhibition and VEGF depletion.
- VEGFR-2 inhibition is a viable therapeutic strategy for malignant gliomas.
- Retrovirus-mediated gene transfer showed no adverse morphological effects in tissues after 6 months.