Experimental Therapeutics and Drug/Chemical Resistance

 The efficacy of therapeutic agents, as well as the toxicity of environmental chemicals is determined by their biological mechanisms of action at the cellular and physiological levels.  These mechanisms may be augmented or reduced by modifying factors such as metabolism of the drug or toxin by cellular enzymes, uptake or removal of the compound by transporters, and the ability of cells to repair or bypass the affected cellular targets.  Research in Dr. Suzy Torti’s lab has two major areas of focus.  One project concerns how a novel iron binding compound kills cancer cells, and whether it can be used as a clinically effective chemotherapeutic drug.  A second project in her lab is aimed at testing and understanding the mechanisms of new agents synthesized by Dr. Mark Welker in the WFU Chemistry Department that induce the cell to make enzymes that help prevent DNA damage and cancer by metabolic inactivation of reactive chemicals.  Research in Dr. Alan Townsend’s lab utilizes genetically engineered cell lines as a tool to aid in understanding the functions and interactions of key enzymes that catalyze the activation and detoxification of drugs or carcinogens.  One project in his lab examines the competition between activation of carcinogens by cytochrome P450 mixed-function oxidases and subsequent detoxification of the reactive products by glutathione S-transferases (GSTs).  A second project revolves around the role of aldehyde dehydrogenases in protection against highly toxic aldehydes generated by oxidative damage to cellular lipids.  Research in Dr. Charles Morrow’s lab is focused on the metabolic cooperation between detoxification by glutathione S-transferases and transmembrane transport “multidrug resistance proteins” (MRPs) that cause drug resistance in cancer cells.  The expression of both the conjugation and transport pathways may have additive or synergistic protective effects, depending on the drug or toxin being studied and the specific isozymes of GST or MRP expressed in model cell lines by stable transfection.  Together, the research in this section of the Biochemistry Department addresses a broad range of important questions regarding the biochemical pathways that govern the metabolism and cellular disposition of reactive chemicals and the resulting mechanisms of toxicity following environmental or therapeutic exposure of cells.

OTEO 562 (a novel chemopreventive agent)