INHIBITORS OF VEGF-INDUCED ANGIOGENESIS AS ANTI-TUMOR DRUGS

THE GROWTH OF SOLID TUMORS IS DEPENDENT ON THE DEVELOPMENT OF NEW VASCULATURE FOR ITS SUPPLY OF NUTRIENTS AND OXYGEN. TUMOR CELLS INDUCE THE OUTGROWTH OF NEW CAPILLARY VESSELS BY PRODUCING DIFFUSIBLE ANGIOGENIC FACTORS. IN THE NORMAL ADULT, ANGIOGENESIS IS A PROCESS PRIMARILY ASSOCIATED WITH WOUND HEALING AFTER INJURY, AND THEREFORE IN THE ABSENCE OF SUCH INJURY THERAPEUTIC AGENTS AIMED AT INHIBITING TUMOR ANGIOGENESIS ARE UNLIKELY TO HAVE DRASTIC SIDE EFFECTS. THE MAJORITY OF CURRENT CANCER THERAPEUTICS ARE CYTOTOXIC AGENTS WHICH HAVE VERY DELETERIOUS EFFECTS ON THE RAPIDLY8DIVIDING CELLS OF THE HEMATOPOIETIC AND GASTRONINTESTINAL SYSTEMS. AMONG THE KNOWN ANGIOGENIC FACTORS, VACULAR ENDOTHELIAL GROWTH FACTOR (VEGF) IS LIKELY TO PLAY A CRITICAL ROLE. VEGF IS SECRETED BY A VARIETY OF TUMOR CELLS, IS A SPECIFIC MITOGEN FOR ENDOTHELIAL CELLS, INCREASES VASCULAR PERMEABILITY AND THUS NUTRIENT AVAILABILITY, AND IS ANGIOGENIC IN VIVO. THE PRINCIPAL OBJECTIVE IS TO IDENTIFY NOVEL INHIBITORS OF VEGF GENE EXPRESSION FOR USE AS POTENTIAL THERAPEUTIC AGENTS. THE EXPERIMENTAL APPROACH WILL UTILIZE A CELL LINE STABLY TRANSFECTED WITH VEGF GENE REGULATORY SEQUENCES LINKED TO A REPORTER GENE TO DETECT ACTIVE COMPOUNDS IN CHEMICAL FILES OR NATURLA PRODUCT EXTRACTS. A FULLY-AUTOMATED HIGH-THROUGHPUT SCREEN WILL BE DEVELOPED FOR THIS PURPOSE.