Drug resistance is a major problem in treating a variety of diseases including cancer. Members of my lab are working to better understand how cells become resistant to two different types of anti-cancer agents, namely ruthenium complexes and ether lipid drugs.
Metal-based drugs have long been used in cancer chemotherapy, because these compounds readily damage the DNA of rapidly dividing cells, ultimately causing these cells to die. Ruthenium-based compounds have the added advantage that with different ligands, the oxidation state of ruthenium can be fine-tuned so that these complexes selectively target hypoxic cells like those found in solid tumors (1). In collaboration with Dr. Laura Stultz, students synthesize various ruthenium complexes and subsequently test the ability of these drugs to kill rapidly growing yeast cells, which serve as a model for cancer. Students also study genetic alterations that result in resistance to these ruthenium-based drugs.
Ether lipid drugs are members of the "second generation" of cancer chemotherapies, because they do not attack the DNA of cancer cells. Instead, ether lipid drugs have a variety of other intracellular targets, including phospholipase C, and protein kinase C (2). In addition to identifying and characterizing mutant strains of yeast that are resistant to ether lipid drugs, students use molecular modeling to learn how these drugs interact with target enzymes. Information gained from such computational studies have potential to facilitate future drug design.
(1) Clarke, M.J. (1999) Non-platinum chemotherapeutic metallopharmaceuticals. Chem. Rev. 99: 2511-2533.
(2) Brachwitz, H. and C. Vollgraff (1995) Analogs of alkyllysophospholipids: Chemistry, effects on the molecular level, and their consequences for normal and malignant cells. Pharmac. Ther. 66: 39-82.
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