ENDOTHELIAL CELL TARGETED CANCER TREATMENT

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Endothelial cells are induced to proliferate under the influence of factors released from tumor cells. This project seeks to identify aspects of the response to these factors on the part of endothelial cells and to use this information as a basis for developing novel cancer treatments which influence endothelial cell function. Using cultures of primary human umbilical vein endothelial cells, specific goals for this project include the definition of agents with selective toxicity for proliferating normal endothelial cells; a definition of cell surface determinants on proliferating endothelial cells, as these molecules could be developed as targets for the delivery of selectively toxic molecules; more detailed characterization of cell proliferation markers, including cell proliferation-related antigens, examination of endothelial cell response pathways which might mediate anti-tumor activity, including the nitric oxide generating system, and elaboration of pro-coagulant activities; examination of the role played by endothelial cells in the elaboration of toxicities observed by various biological response modifiers including cytokine-induced destabilization of cellular junctions; and alteration of endothelial cell sensitivity to antiproliferative agents in response to cytokines and toxins. Recent studies have defined the potent capacity of cucurbitacins to inhibit endothelial cell proliferation especially cucurbitacin E (NSC 106399) by a mechanism that may disrupt the actin cytoskeleton. However, convincing biologic effects of cucurbitacin to demonstrate anti-angiogenic activity in vivo has not been accomplished. Using the PCR-based strategies of differentially displayed mRNA amplification, candidate genes differentially expressed in proliferating endothelial cells have been defined.