Current Research: The emergence of antineoplastic drug resistance constitutes a major problem in the successful treatment of disseminated cancer. Frequently, in both clinical and experimental systems of anticancer drug treatment, exposure to one anticancer drug results in the development of cancer cells that are resistant to multiple drugs in addition to the selecting drug used in treatment. This phenomenon is termed multidrug resistance (MDR) and is associated with the increased expression of a number of genes believed to contribute to the MDR phenotype. A major focus of my research concerns the role of combined actions of glutathione transferases (GST) and the multidrug resistance protein (MRP) family efflux transporters in the emergence of anticancer drug resistance and carcinogen detoxification. I am investigating the interplay between the drug/toxin conjugating GST isozymes and MRP family members. Using a variety of model cell lines developed in our laboratory, I am examining the hypothesis that MRP and GST act synergistically to confer MDR. Additionally, I am investigating the role in protection from carcinogen and other xenobiotics toxicities played by combined expression of xenobiotic conjugating and drug efflux systems. Recently, we have begun investigations on the role of glutathione conjugation and conjugate efflux in the modulation of the biological, including anti-tumor, activities of potent cellular eicosinoids. Recent Publications: Kushman ME, Kabler SL, Fleming MH, Ravoori S, Gupta RC, Doehmer J, Morrow CS, Townsend AJ. Expression of human glutathione S-transferase P1 confers resistance to benzo [a]pyrene or benzo[a]pyrene-7,8-dihydrodiol mutagenesis, macromolecular alkylation, and formation of stable N2-Gua-BPDE adducts in stably transfected V79MZ cells co-expressing hCYP1A1. Carcinogenesis. 2006 Aug 2. Alexander RL, Bates DJ, Wright MW, King SB, Morrow CS. Modulation of nitrated lipid signaling by multidrug resistance protein 1 (MRPI): glutathione conjugation and MRP1-mediated efflux inhibit nitrolinoleic acid-induced, PPARgamma-dependent transcription activation. Biochemistry. 2006 Jun 27;45(25):7889-96. Morrow CS, Peklak-Scott C, Bishwokarma B, Kute TE, Smitherman PK, Townsend AJ. Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol Pharmacol. 2006 Apr;69(4):1499-505. Epub 2006 Jan 24. O’Flaherty JT, Rogers LC, Paumi CM, Hantgan RR, Thomas LR, Clay CE, High K, Chen YQ, Willingham MC, Smitherman PK, Kute TE, Rao A, Cramer SD, Morrow CS. 5-Oxo-ETE analogs and the proliferation of cancer cells. Biochim Biophys Acta. 2005 Oct 1;1736(3):228-36. Epub 2005 Aug 30. Riddick DS, Lee C, Ramji S, Chinje EC, Cowen RL, Williams KJ, Patterson AV, Stratford IJ, Morrow CS, Townsend AJ, Jounaidi Y, Chen CS, Su T, Lu H, Schwartz PS, Waxman DJ. Cancer chemotherapy and drug metabolism. Drug Metab Dispos. 2005 Aug;33(8):1083-96. Publications:
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