GLUTATHIONE S TRANSFERASE & ITS REGULATION OF CARCINOGENIC ELECTROPHILES

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We are studying glutathione S-transferase and its regulation of carcinogenic electrophiles. Liposome-mediated delivery of rGST (glutathione S-transferase) may be used to protect gastrointestinal cells. Our current effort is directed toward the delivery of forced-evolution GST molecules to the epithelial cells which line the lurnen of the upper GI tract using synthetic liposomes. Some liposome parameters that are being optimized include: size/internal. volume, external membrane charge, presence of external membrane docking molecules, coating of the external membrane to inhibit lipase degradation, pH sensitivity of lipids to foster liposome dissolution in endosomes, and the presence of recombinant molecules in the liposome contents to foster-breakage of endosomes and delivery of the liposome contents to cytosol. Transient fortification of upper-GI cells with rGST/GSH could provide a means to protect these cells during systemic cancer chemotherapy with short half-life nitrogen mustards such as melphalan, cyclophosphamide or chlorambucil. Our current, initial experiments involve treating GI cells in tissue culture where the cells are adhered to cover slips and then treated with liposome suspensions. Our goal is to study liposome adherence and deposition of liposome contents into the cultured cells. We plan to use confocal microscopy to monitor delivery of molecules into epithelial cells.