Antiangiogenic gene therapy in a rat glioma model using a dominant-negative vascular endothelial growth factor receptor 2.
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.
Machein
M R
MR
Department of Neuropathology, Freiburg University Medical School, Germany.
Risau
W
W
Plate
K H
KH
D000818:Animals; D015139:Blotting, Southern; D001932:Brain Neoplasms / Q000098:blood supply / Q000401:mortality / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005910:Glioma / Q000098:blood supply / Q000401:mortality / Q000628:therapy*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009389:Neovascularization, Pathologic / Q000628:therapy*; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D017978:Receptors, Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor