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Kenneth D Tew, PhD
Professor of Cell and Molecular Pharmacology
College of Medicine
MUSC

Email: tewk@musc.edu
 
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Kenneth D Tew, PhD

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Research Interest:

My research employs an essential platform that interrogates redox pathways (with special emphasis on glutathione homeostasis) in drug discovery/development, drug resistance and biomarker identification in cancer. Preclinical pharmacology centers on new agents that induce stress response through liberation of reactive oxygen or nitrogen species. In oncology, there is a critical need to identify new drugs with clinical utility and biomarkers that correlate with pharmacokinetics/ pharmacodynamics and apply these to predictive drug responses. Recently, my research has focused upon specific post-translationally modified, S-glutathionylated proteins that influence cell-signaling pathways and may also serve as surrogate plasma biomarkers for response to drugs that induce oxidative and nitrosative stress. Translational research efforts have resulted in one glutathione S-transferase activated prodrug and two small molecule drugs that are under clinical development as possible myeloproliferative agents.

Honors:
John C. West Endowed Chair in Translational Cancer Therapeutics, SmartState Center of Economic Excellence

Positions:
Co-Leader, Developmental Cancer Therapeutics Program, Hollings Cancer Center, Medical University of South Carolina
Chair, Department of Cell & Molecular Pharmacology, Medical University of South Carolina

Selected Publications:

1.Manevich Y, Hutchens S, Halushka PV, Tew KD, Townsend DM, Jauch EC, Borg K. Peroxiredoxin VI oxidation in cerebrospinal fluid correlates with traumatic brain injury outcome. Free Radic Biol Med. .72:210-21, 2014. PMCID: PMC4088265
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2.Zhang J, Grek C, Ye ZW, Manevich Y, Tew KD, Townsend DM. Pleiotropic functions of glutathione S-transferase P. Adv Cancer Res. .122:143-75, 2014.
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3.Grek CL, Zhang J, Manevich Y, Townsend DM, Tew KD. Causes and consequences of cysteine S-glutathionylation. J Biol Chem. .288(37):26497-504, 2013. PMCID: PMC3772197
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4.Manevich Y, Hutchens S, Tew KD, Townsend DM. Allelic variants of glutathione S-transferase P1-1 differentially mediate the peroxidase function of peroxiredoxin VI and alter membrane lipid peroxidation. Free Radic Biol Med. .54:62-70, 2012. PMCID: PMC3539142
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5.Bowers RR, Manevich Y, Townsend DM, Tew KD. Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility. Biochemistry. .51(39):7740-54, 2012. PMCID: PMC3472422
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6.Mack JT, Brown CB, Garrett TE, Uys JD, Townsend DM, Tew KD. Ablation of the ATP-binding cassette transporter, Abca2 modifies response to estrogen-based therapies. Biomed Pharmacother. .66(6):403-8, 2012. PMCID: PMC3714854
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7.Anathy V, Roberson E, Cunniff B, Nolin JD, Hoffman S, Spiess P, Guala AS, Lahue KG, Goldman D, Flemer S, van der Vliet A, Heintz NH, Budd RC, Tew KD, Janssen-Heininger YM. Oxidative processing of latent Fas in the endoplasmic reticulum controls the strength of apoptosis. Mol Cell Biol. .32(17):3464-78, 2012. PMCID: PMC3422013
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8.Tew KD, Townsend DM. Glutathione-s-transferases as determinants of cell survival and death. Antioxid Redox Signal. .17(12):1728-37, 2012. PMCID: PMC3474190
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9.Calpe-Berdiel L, Zhao Y, de Graauw M, Ye D, van Santbrink PJ, Mommaas AM, Foks A, Bot M, Meurs I, Kuiper J, Mack JT, Van Eck M, Tew KD, van Berkel TJ. Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice. Atherosclerosis. .223(2):332-41, 2012.
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10.Xiong Y, Manevich Y, Tew KD, Townsend DM. S-Glutathionylation of Protein Disulfide Isomerase Regulates Estrogen Receptor a Stability and Function. Int J Cell Biol. .2012:273549, 2012. PMCID: PMC3359683
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11.Grünewald E, Tew KD, Porteous DJ, Thomson PA. Developmental expression of orphan G protein-coupled receptor 50 in the mouse brain. ACS Chem Neurosci. .3(6):459-72, 2012. PMCID: PMC3382458
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12.Grek CL, Townsend DM, Uys JD, Manevich Y, Coker WJ, Pazoles CJ, Tew KD. S-glutathionylated serine proteinase inhibitors as plasma biomarkers in assessing response to redox-modulating drugs. Cancer Res. .72(9):2383-93, 2012.
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13.Tew KD. NrF2 /Keap1 as gatekeepers of redox homeostasis – do they prevent or cause cancer? Pigment Cell Melanoma Res. .24(6):1078-9, 2011.
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14.Tew KD. Drug resistance in cancer. Editorial. Biochem Pharmacol. .83(8):985-6, 2011.
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15.Michaki V, Guix FX, Vennekens K, Munck S, Dingwall C, Davis JB, Townsend DM, Tew KD, Feiguin F, De Strooper B, Dotti CG, Wahle T. Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-ß production by altering Nicastrin maturation and intracellular localization. J Biol Chem. .287(2):1100-11, 2011. PMCID: PMC3256850
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16.Uys JD, Knackstedt L, Hurt P, Tew KD, Manevich Y, Hutchens S, Townsend DM, Kalivas PW. Cocaine-induced adaptations in cellular redox balance contributes to enduring behavioral plasticity. Neuropsychopharmacology. .36(12):2551-60, 2011. PMCID: PMC3194081
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17.Xiong Y, Uys JD, Tew KD, Townsend DM. S-glutathionylation: from molecular mechanisms to health outcomes. Antioxid Redox Signal. .15(1):233-70, 2011. PMCID: PMC3110090
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18.Tew KD, Manevich Y, Grek C, Xiong Y, Uys J, Townsend DM. The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer. Free Radic Biol Med. .51(2):299-313, 2011. PMCID: PMC3125017
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19.Tew KD, Townsend DM. Regulatory functions of glutathione S-transferase P1-1 unrelated to detoxification. Drug Metab Rev. .43(2):179-93, 2011.
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20.Manevich Y, Townsend DM, Hutchens S, Tew KD. Diazeniumdiolate mediated nitrosative stress alters nitric oxide homeostasis through intracellular calcium and S-glutathionylation of nitric oxide synthetase. PLoS One. .5(11):e14151, 2010. PMCID: PMC2994766
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21.Tew KD, Townsend DM. Redox platforms in cancer drug discovery and development. Curr Opin Chem Biol. .15(1):156-61, 2010. PMCID: PMC3073687
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22.Mack JT, Helke KL, Normand G, Green C, Townsend DM, Tew KD. ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration. Cancer Lett. .300(2):154-61, 2010. PMCID: PMC2994978
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23.Grek CL, Townsend DM, Tew KD. The impact of redox and thiol status on the bone marrow: Pharmacological intervention strategies. Pharmacol Ther. .129(2):172-84, 2010. PMCID: PMC3026067
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24.Grek CL, Tew KD. Redox metabolism and malignancy. Curr Opin Pharmacol. .10(4):362-8, 2010. PMCID: PMC2930777
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25.Hutchens S, Manevich Y, He L, Tew KD, Townsend DM. Cellular resistance to a nitric oxide releasing glutathione S-transferase P-activated prodrug, PABA/NO. Invest New Drugs. .29(5):719-29, 2010. PMCID: PMC2912140
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26.Uys JD, Manevich Y, Devane LC, He L, Garret TE, Pazoles CJ, Tew KD, Townsend DM. Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic. Biomed Pharmacother. .64(7):493-8, 2010. PMCID: PMC2921589
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27.Jenderny S, Lin H, Garrett T, Tew KD, Townsend DM. Protective effects of a glutathione disulfide mimetic (NOV-002) against cisplatin induced kidney toxicity. Biomed Pharmacother. .64(1):73-6, 2009. PMCID: PMC3388846
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28.Townsend DM, Manevich Y, He L, Xiong Y, Bowers RR, Hutchens S, Tew KD. Nitrosative stress-induced s-glutathionylation of protein disulfide isomerase leads to activation of the unfolded protein response. Cancer Res. .69(19):7626-34, 2009. PMCID: PMC2756322
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29.Townsend DM, Manevich Y, He L, Hutchens S, Pazoles CJ, Tew KD. Novel role for glutathione S-transferase pi. Regulator of protein S-Glutathionylation following oxidative and nitrosative stress. J Biol Chem. .284(1):436-45, 2008. PMCID: PMC2610519
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30.Townsend DM, Tew KD. Pharmacology of a mimetic of glutathione disulfide, NOV-002. Biomed Pharmacother. .63(2):75-8, 2008. PMCID: PMC2657662
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31.Townsend DM, Tew KD, He L, King JB, Hanigan MH. Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity. Biomed Pharmacother. .63(2):79-85, 2008. PMCID: PMC2667699
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32.Townsend DM, Pazoles CJ, Tew KD. NOV-002, a mimetic of glutathione disulfide. Expert Opin Investig Drugs. .17(7):1075-83, 2008.
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33.Lei K, Townsend DM, Tew KD. Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug response. Oncogene. .27(36):4877-87, 2008. PMCID: PMC3399212
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34.Townsend DM, He L, Hutchens S, Garrett TE, Pazoles CJ, Tew KD. NOV-002, a glutathione disulfide mimetic, as a modulator of cellular redox balance. Cancer Res. .68(8):2870-7, 2008. PMCID: PMC3397193
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35.Mack JT, Brown CB, Tew KD. ABCA2 as a therapeutic target in cancer and nervous system disorders. Expert Opin Ther Targets. .12(4):491-504, 2008.
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36.Mack JT, Townsend DM, Beljanski V, Tew KD. The ABCA2 transporter: intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compounds. Curr Drug Metab. .8(1):47-57, 2007.
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37.Mack JT, Beljanski V, Soulika AM, Townsend DM, Brown CB, Davis W, Tew KD. "Skittish" Abca2 knockout mice display tremor, hyperactivity, and abnormal myelin ultrastructure in the central nervous system. Mol Cell Biol. .27(1):44-53, 2006. PMCID: PMC1800669
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38.Tew KD. Redox in redux: Emergent roles for glutathione S-transferase P (GSTP) in regulation of cell signaling and S-glutathionylation. Biochem Pharmacol. .73(9):1257-69, 2006.
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39.Mack JT, Beljanski V, Tew KD, Townsend DM. The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking. Biomed Pharmacother. .60(9):587-92, 2006.
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40.Findlay VJ, Townsend DM, Morris TE, Fraser JP, He L, Tew KD. A novel role for human sulfiredoxin in the reversal of glutathionylation. Cancer Res. .66(13):6800-6, 2006.
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41.McIlwain CC, Townsend DM, Tew KD. Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene. .25(11):1639-48, 2006.
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42.Saavedra JE, Srinivasan A, Buzard GS, Davies KM, Waterhouse DJ, Inami K, Wilde TC, Citro ML, Cuellar M, Deschamps JR, Parrish D, Shami PJ, Findlay VJ, Townsend DM, Tew KD, Singh S, Jia L, Ji X, Keefer LK. PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity. J Med Chem. .49(3):1157-64, 2006.
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43.Townsend DM, Findlay VJ, Fazilev F, Ogle M, Fraser J, Saavedra JE, Ji X, Keefer LK, Tew KD. A glutathione S-transferase pi-activated prodrug causes kinase activation concurrent with S-glutathionylation of proteins. Mol Pharmacol. .69(2):501-8, 2005.
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44.Tucker JM, Lipatova Z, Beljanski V, Townsend DM, Tew KD. Evaluation of lipophilins as determinants of tumor cell response to estramustine. J Pharmacol Exp Ther. .315(3):1158-62, 2005.
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45.Tew KD. TLK-286: a novel glutathione S-transferase-activated prodrug. Expert Opin Investig Drugs. .14(8):1047-54, 2005.
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46.Beljanski V, Soulika A, Tucker JM, Townsend DM, Davis W, Tew KD. Characterization of the ATPase activity of human ATP-binding cassette transporter-2 (ABCA2). In Vivo. .19(4):657-60, 2005.
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47.Gate L, Majumdar RS, Lunk A, Tew KD. Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice. Int J Cancer. .113(1):29-35, 2005.
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48.Townsend DM, Findlay VL, Tew KD. Glutathione S-transferases as regulators of kinase pathways and anticancer drug targets. Methods Enzymol. .401:287-307, 2005.
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49.Tew KD, Boyd JT, Chen ZJ, Davis W, Fazilev F, Findlay V, Gaté L, Ile K, Soulika A, Townsend DM. Glutathione and ABC transporters as determinants of sensitivity to oxidative and nitrosative stress. J Nutr. .134(11):3205S-3206S, 2004.
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50.Davis W, Boyd JT, Ile KE, Tew KD. Human ATP-binding cassette transporter-2 (ABCA2) positively regulates low-density lipoprotein receptor expression and negatively regulates cholesterol esterification in Chinese hamster ovary cells. Biochim Biophys Acta. .1683(1-3):89-100, 2004.
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51.Boonstra R, Timmer-Bosscha H, van Echten-Arends J, van der Kolk DM, van den Berg A, de Jong B, Tew KD, Poppema S, de Vries EG. Mitoxantrone resistance in a small cell lung cancer cell line is associated with ABCA2 upregulation. Br J Cancer. .90(12):2411-7, 2004. PMCID: PMC2409533
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52.Chen ZJ, Vulevic B, Ile KE, Soulika A, Davis W, Reiner PB, Connop BP, Nathwani P, Trojanowski JQ, Tew KD. Association of ABCA2 expression with determinants of Alzheimer's disease. FASEB J. .18(10):1129-31, 2004.
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53.Findlay VJ, Townsend DM, Saavedra JE, Buzard GS, Citro ML, Keefer LK, Ji X, Tew KD. Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. Mol Pharmacol. .65(5):1070-9, 2004.
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54.Ile KE, Davis W, Boyd JT, Soulika AM, Tew KD. Identification of a novel first exon of the human ABCA2 transporter gene encoding a unique N-terminus. Biochim Biophys Acta. .1678(1):22-32, 2004.
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55.Tapiero H, Townsend DM, Tew KD. Organosulfur compounds from alliaceae in the prevention of human pathologies. Biomed Pharmacother. .58(3):183-93, 2004.
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56.Tapiero H, Townsend DM, Tew KD. The role of carotenoids in the prevention of human pathologies. Biomed Pharmacother. .58(2):100-10, 2004.
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57.Tew KD. Small molecule inhibition of hypoxia inducible factor-1alpha: a viable therapeutic approach? Mol Cancer Ther. .3(3):245-6, 2004.
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58.Townsend DM, Tew KD, Tapiero H. Sulfur containing amino acids and human disease. Biomed Pharmacother. .58(1):47-55, 2004.
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59.Gate L, Majumdar RS, Lunk A, Tew KD. Increased myeloproliferation in glutathione S-transferase pi-deficient mice is associated with a deregulation of JNK and Janus kinase/STAT pathways. J Biol Chem. .279(10):8608-16, 2003.
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60.Tapiero H, Townsend DM, Tew KD. Trace elements in human physiology and pathology. Copper. Biomed Pharmacother. .57(9):386-98, 2003.
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61.Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. .22(47):7369-75, 2003.
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62.Tapiero H, Townsend DM, Tew KD. Phytosterols in the prevention of human pathologies. Biomed Pharmacother. .57(8):321-5, 2003.
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63.Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Funk JO. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol. .64(2):382-94, 2003.
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64.Chen ZJ, Gaté L, Davis W, Ile KE, Tew KD. Sensitivity and fidelity of DNA microarray improved with integration of Amplified Differential Gene Expression (ADGE). BMC Genomics. .4(1):28, 2003. PMCID: PMC179896
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65.Gaté L, Lunk A, Tew KD. Resistance to phorbol 12-myristate 13-acetate-induced cell growth arrest in an HL60 cell line chronically exposed to a glutathione S-transferase pi inhibitor. Biochem Pharmacol. .65(10):1611-22, 2003.
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66.Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother. .57(3-4):145-55, 2003.
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67.Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharmacother. .57(3-4):134-44, 2003.
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68.Davis W, Chen ZJ, Ile KE, Tew KD. Reciprocal regulation of expression of the human adenosine 5'-triphosphate binding cassette, sub-family A, transporter 2 (ABCA2) promoter by the early growth response-1 (EGR-1) and Sp-family transcription factors. Nucleic Acids Res. .31(3):1097-107, 2003. PMCID: PMC149212
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69.Townsend D, Tew K. Cancer drugs, genetic variation and the glutathione-S-transferase gene family. Am J Pharmacogenomics. .3(3):157-72, 2003.
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70.Chen ZJ, Gaté L, Davis W, Ile KE, Tew KD. Integration of amplified differential gene expression (ADGE) and DNA microarray. IUBMB Life. .54(6):335-8, 2002.
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71.Townsend DM, Shen H, Staros AL, Gaté L, Tew KD. Efficacy of a glutathione S-transferase pi-activated prodrug in platinum-resistant ovarian cancer cells. Mol Cancer Ther. .1(12):1089-95, 2002.
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72.Ruscoe JE, Rosario LA, Wang T, Gaté L, Arifoglu P, Wolf CR, Henderson CJ, Ronai Z, Tew KD. Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther. .298(1):339-45, 2001.
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73.Shen H, Chen ZJ, Zilfou JT, Hopper E, Murphy M, Tew KD. Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs. J Pharmacol Exp Ther. .297(3):1067-73, 2001.
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74.Chen ZJ, Shen H, Tew KD. Gene expression profiling using a novel method: amplified differential gene expression (ADGE). Nucleic Acids Res. .29(10):E46, 2001. PMCID: PMC55467
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75.Vulevic B, Chen Z, Boyd JT, Davis W, Walsh ES, Belinsky MG, Tew KD. Cloning and characterization of human adenosine 5'-triphosphate-binding cassette, sub-family A, transporter 2 (ABCA2). Cancer Res. .61(8):3339-47, 2001.
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76.Wang T, Arifoglu P, Ronai Z, Tew KD. Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem. .276(24):20999-1003, 2001.
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77.Davis W, Ronai Z, Tew KD. Cellular thiols and reactive oxygen species in drug-induced apoptosis. J Pharmacol Exp Ther. .296(1):1-6, 2001.
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78.Tew KD. Is there a role for glyoxalase I inhibitors as antitumor drugs? Drug Resist Updat. .3(5):263-264, 2000.
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79.O'Brien M, Kruh GD, Tew KD. The influence of coordinate overexpression of glutathione phase II detoxification gene products on drug resistance. J Pharmacol Exp Ther. .294(2):480-7, 2000.
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80.Rosario LA, O'Brien ML, Henderson CJ, Wolf CR, Tew KD. Cellular response to a glutathione S-transferase P1-1 activated prodrug. Mol Pharmacol. .58(1):167-74, 2000.
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81.O'Brien ML, Vulevic B, Freer S, Boyd J, Shen H, Tew KD. Glutathione peptidomimetic drug modulator of multidrug resistance-associated protein. J Pharmacol Exp Ther. .291(3):1348-55, 1999.
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82.Ranganathan S, Ciaccio PJ, Walsh ES, Tew KD. Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation. Gene. .240(1):149-55, 1999.
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83.Shen H, Schultz MP, Tew KD. Glutathione conjugate interactions with DNA-dependent protein kinase. J Pharmacol Exp Ther. .290(3):1101-6, 1999.
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84.Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR, Davis RJ, Ronai Z. Regulation of JNK signaling by GSTp. EMBO J. .18(5):1321-34, 1999. PMCID: PMC1171222
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