TUMOR-GROWTH MODULATION BY SENSE AND ANTISENSE VASCULAR ENDOTHELIAL GROWTH-FACTOR GENE-EXPRESSION - EFFECTS ON ANGIOGENESIS, VASCULAR-PERMEABILITY, BLOOD-VOLUME, BLOOD-FLOW, FLUORODEOXYGLUCOSE UPTAKE, AND PROLIFERATION OF HUMAN-MELANOMA INTRACEREBRAL XENOGRAFTS

Vascular endothelial growth factor (VEGF), also known as vascular perm eability factor, has been investigated as a potent mediator of brain t umor angiogenesis and tumor growth. We evaluated the effect of VEGF ex pression on the pathophysiology of tumor growth in the brain. Human SK -MEL-2 melanoma cells, with minimal VEGF expression, were stably trans fected with either sense or antisense mouse VEGF cDNA and used to prod uce intracerebral xenografts. Vascular permeability, blood volume, blo od flow and tumor fluorodeoxyglucose metabolism were assessed using ti ssue sampling and quantitative autoradiography. Tumor proliferation wa s assessed by measuring bromodeoxyuridine labeling indices. Tumor vasc ular density and morphological status of the blood-brain barrier were evaluated by immunohistochemistry. SK-MEL-2 cells transfected with sen se VEGF (V+) expressed large amounts of mouse and human VEGF protein; V+ cells formed well-vascularized, rapidly growing tumors with minimal tumor necrosis, V+ tumors had substantial and significant increases i n blood volume, blood flow, vascular permeability, and fluorodeoxygluc ose metabolism compared to wild-type and/or V- (antisense VEGF) tumors . VEGF antisense transfected V- expressed no detectable VEGF protein a nd formed minimally vascularized tumors, V- tumors had a very low init ial growth rate with central necrosis; blood volume, blood flow, vascu lar permeability, and glucose metabolism levels were low compared to w ild-type and V+ tumors. A substantial inhibition of intracerebral tumo r growth, as well as a decrease in tumor vascularity, blood flow, and vascular permeability may be achieved by down-regulation of endogenous VEGF expression in tumor tissue. VEGF-targeted antiangiogenic gene th erapy could be an effective component of a combined strategy to treat VEGF-producing brain tumors.