The Glutathione System in Alkylator Resistance

  • David Hamilton
  • Nasser Fotouhi-Ardakani
  • Gerald Batist
Part of the Cancer Treatment and Research book series (CTAR, volume 112)


One of the greatest obstacles in the effective chemotherapy of neoplastic disease is the presence of tumor chemoresistance. In some instances, a tumor can be intrinsically resistant to chemotherapy or, in other cases, develop resistance during the course of antineoplastic treatment. This acquired resistance is thought to occur through the selection of a subpopulation of resistant tumor cells as the tumor is exposed to chemotherapy. To complicate chemotherapeutic drug selection, it has been found that once a tumor demonstrates resistance to one class of drugs, it will often be resistant to other classes that share structural or functional homology


Ethacrynic Acid Glutathione System Human Ovarian Cancer Cell Line Buthionine Sulfoximine Heavy Subunit 
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  1. 1.
    Tew K, Colvin M, Chabner B. Alkylating agents. In: Cancer Chemotherapy and Biotherapy: Principles and Practice, BA Chabner, DL Longo (eds.), Lippincott-Raven, Philadelphia, PA, 1996.Google Scholar
  2. 2.
    Hansson J, Lewensohn R, Ringborg U, Nilsson B. Formation and removal of DNA cross-links induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human melanoma cells. Cancer Res, 47:2631–2637, 1987.PubMedGoogle Scholar
  3. 3.
    Pu Q, Bezwoda W. Induction of alkylator (melphalan) resistance in HL60 cells is accompanied by increased levels of topoisomerase II expression and function. Mol Pharmacol, 56:147–153, 1999.PubMedGoogle Scholar
  4. 4.
    Bedford P, Fichtinger-Schepman AMJ, Hill BT. Differential repair of platinum-DNA adducts in human bladder and testicular tumor continuous cell lines. Cancer Res, 48:3019–3024, 1988.PubMedGoogle Scholar
  5. 5.
    Redwood WR, Colvin M. Transport of melphalan by sensitive and resistant L1210 cells. Cancer Res, 40:1144–1149, 1980.PubMedGoogle Scholar
  6. 6.
    Richon VM, Schulte N, Eastman A. Multiple mechanisms of resistance to cisdiamminedichloroplatinum (II) in murine leukemia L1210 cells. Cancer Res, 47:2056–2061, 1987.PubMedGoogle Scholar
  7. 7.
    Harrison SD Jr, Brockman RW, Trader MWet al.Cross resistance of drug-resistant murine leukemias to deoxyspergualin (NSC 356894) in vivo. Invest New Drugs 5:345–351, 1987.PubMedCrossRefGoogle Scholar
  8. 8.
    Ozols RF, Masuda H, Hamilton TC. Mechanisms of cross-resistance between radiation and antineoplastic drugs. NCI Monogr, 6:159–165, 1988.PubMedGoogle Scholar
  9. 9.
    McGown AT, Fox BW. A proposed mechanism of resistance to cyclophosphamide and phosphoramide mustard in a Yoshida cell line in vitro. Cancer Res, 17:223–226, 1986.Google Scholar
  10. 10.
    Schecter RL, Alaoui-Jamali MA, Batist G. Glutathione S-transferase in chemotherapy resistance and in carcinogenesis. Biochem Cell Biol, 70:349–353, 1991.CrossRefGoogle Scholar
  11. 11.
    Tew, K. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res, 54:4313–4320, 1994.PubMedGoogle Scholar
  12. 12.
    Meister A. Metabolism and function of glutathione. In: Glutathione: Chemical, Biochemical and Medical Aspects, D Dolphin, A Avramovich, R Poulson (eds.), John Wiley and Sons, New York, NY, 1989.Google Scholar
  13. 13.
    Kosower NS, Kosower ES. The glutathione-glutathione disulfide system. In: Free Radicals in Biology, WA Pryor (ed.), Academic Press, New York, NY, 1976.Google Scholar
  14. 14.
    Kosower NS, Kosower ES. Glutathione metabolism and function. Annu Rev Biochem, 52:711–760, 1983.CrossRefGoogle Scholar
  15. 15.
    Hanawalt PC, Cooper PK, Ganesan AK. DNA repair in bacterial and mammalian cells. Annu Rev Biochem, 48:783–836, 1979.PubMedCrossRefGoogle Scholar
  16. 16.
    Masuda H, Ozols RF, Lai GM. Increased DNA repair as a mechanism of acquired resistance to cis-diamminedichloroplatinum (II) in human ovarian cancer cell lines. Cancer Res, 48:5713–5716, 1988.PubMedGoogle Scholar
  17. 17.
    Luperchio S, Tamir S, Tannenbaum SR. NO-induced oxidative stress and glutathione metabolism in rodent and human cells. Free Radic Biol Med, 21:513–519, 1996.PubMedCrossRefGoogle Scholar
  18. 18.
    Tu Z, Anders MW. Identification of an important cysteine residue in human glutamatecysteine ligase catalytic subunit by site-directed mutagenesis. Biochem J, 336:675–680, 1998.PubMedGoogle Scholar
  19. 19.
    Aslund F, Beckwith J. Bridge over troubled waters: sensing stress by disulfide bond formation. Cell, 96:751–753, 1999.PubMedCrossRefGoogle Scholar
  20. 20.
    Zheng M, Aslund F, Storz G. Activation of the OxyR transcription factor by reversible disulfide bond formation. Science, 279:1718–1721, 1998.PubMedCrossRefGoogle Scholar
  21. 21.
    Mulcahy RT, Wartman MA, Bailey HH, Gipp JJ. Constitutive and beta-naphthoflavoneinduced expression of the human gamma-glutamylcysteine synthetase heavy subunit gene is regulated by a distal antioxidant response element/TRE sequence. J Biol Chem, 272:7445–7454, 1997.PubMedCrossRefGoogle Scholar
  22. 22.
    Wild A, Moinova H, Mulcahy T. Regulation of y-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem, 274:33627–33636, 1999.PubMedCrossRefGoogle Scholar
  23. 23.
    Wild AC, Mulcahy T. Regulation of y-glutamylcysteine synthetase subunit gene expression: insight into transcriptional control of antioxidant defenses. Free Radic Res, 32:281–301, 2000.PubMedCrossRefGoogle Scholar
  24. 24.
    Kondo T, Higashiyama Y, Goto Set al.Regulation of y-glutamylcysteine synthetase expression in response to oxidative stress. Free Radic Res, 31:325–334, 1999.PubMedCrossRefGoogle Scholar
  25. 25.
    Walsh AC, Li W, Rosen DR, Lawrence DA. Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of y-glutamylcysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5’ untranslated region. Cytognent Cell Genet, 75:14–16, 1996.CrossRefGoogle Scholar
  26. 26.
    Beutler E, Gelbart T, Kondo T, Matsunaga AT. The molecular basis of a case of yglutamylcysteine synthetase deficiency. Blood, 94:2890–2894, 1999.PubMedGoogle Scholar
  27. 27.
    Ristoff E, Augustson C, Geissler Jet al.A missense mutation in the heavy subunit of yglutamylcysteine synthetase gene causes hemolytic anemia. Blood, 95:2193–2197, 2000.PubMedGoogle Scholar
  28. 28.
    Booth J, Boyland E, Sims P. An enzyme from rat liver catalysing conjugation with glutathione. Biochem J, 79:516–524, 1961.PubMedGoogle Scholar
  29. 29.
    Hubatsch I, Riddrestrom M, Mannervik B. Human glutathione transferase A4–4: an Alpha class enzyme with high catalytic efficiency in the conjugation of 4- hydroxynonenal and other genotoxic products of lipid peroxidation. Biochem J, 330:175–179, 1998.PubMedGoogle Scholar
  30. 30.
    Baez S, Segura-Aguilar J, Widersten Met al.Glutathione transferases catalyse the detoxification of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem J, 324:25–28, 1997.PubMedGoogle Scholar
  31. 31.
    Berhane K, Widersten M, Engstrom Aet al.Detoxification of base propenals and other alpha, beta-unsaturated aldehyde products of radical reactions and lipid peroxidation by human glutathione transferases. Proc Natl Acad Sci. USA, 91:1480–1484, 1994.PubMedCrossRefGoogle Scholar
  32. 32.
    Mannervik B, Alin P, Guthenberg Cet al.Identification of three classes of cytosolic glutathione transferase common to several mammalian species: correlation between structural data and enzymatic properties. Proc Natl Acad Sci USA, 82:7202–7206, 1995.CrossRefGoogle Scholar
  33. 33.
    Morgenstern R, Guthenburg C, Depierre JW. Microsomal glutathione S-transferase. Purification, initial characterisation and demonstration that it is not identical to the cytosolic glutathione S-transferases A, B and C. Eur J Biochem, 128:243–248, 1982.Google Scholar
  34. 34.
    Jakobsson PJ, Mancini JA, Ford-Hutchinson AW. Identification and characterization of a novel human microsomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase. J Biol Chem, 271:22203–22210, 1996.PubMedCrossRefGoogle Scholar
  35. 35.
    DeJong JL, Morgenstern R, Jomvall Het al.Gene expression of rat and human microsomal glutathione S-transferases. J Biol Chem, 263:8430–8436, 1998.Google Scholar
  36. 36.
    Lam BK, Penrose JF, Freeman GJ, Austen KF. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci USA, 91:7663–7667, 1994.PubMedCrossRefGoogle Scholar
  37. 37.
    Arca P, Hardisson C, Suarez JE. Purification of a glutathione S-transferase that mediates fosfomycin resistance in bacteria. Antimicrob Agents Chemother, 34:844–848, 1990.PubMedCrossRefGoogle Scholar
  38. 38.
    Mannervik B, Danielson UH. Glutathione transferases-structure and catalytic activities. Crit Dev Biochem, 23:283–337, 1998.CrossRefGoogle Scholar
  39. 39.
    Bolton MG, Colvin OM, Hilton J. Specificity of isozymes of murine hepatic glutathione S-transferase for the conjugation of glutathione with L-phenylalanine mustard. Cancer Res, 51:2410–2414, 1991.PubMedGoogle Scholar
  40. 40.
    Yuan Z-M, Fenselau C, Dulik DM, Martin Wet al.Laser desorption electron impact: application to a study of the mechanism of conjugation of glutathione and cyclophosphamide. Anal Chem, 62:868–870, 1990.PubMedCrossRefGoogle Scholar
  41. 41.
    Ciaccio PJ, Tew KD, LaCreta FP. The spontaneous and glutathione S-transferase mediated reaction of chlorambucil with glutathione. Cancer Commun, 2:279–286, 1990.PubMedGoogle Scholar
  42. 42.
    Zimniak P, Nanduri B, Pikula Set al.Naturally occurring human glutathione Stransferase GSTP1–1 isoforms with isoleucine and valine in position 104 differ in enzymatic properties. Eur J Biochem, 224:893–899, 1994.PubMedCrossRefGoogle Scholar
  43. 43.
    Coles B, Ketterer B. The role of glutathione and glutathione transferases in chemical carcinogenesis. Biochem Mol Biol, 25:47–70, 1990.CrossRefGoogle Scholar
  44. 44.
    Cole SPC, Bhardwaj G, Gerlach JHet al.Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science, 258:1650–1654, 1992.PubMedCrossRefGoogle Scholar
  45. 45.
    Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem, 17:463–468, 1992.CrossRefGoogle Scholar
  46. 46.
    Leier I, Jedlitschky G, Buchholz Uet al.ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. Biochem J, 314:433–437, 1996.PubMedGoogle Scholar
  47. 47.
    Jedlitschky G, Leier I, Buchholz Uet al.Transport of glutathione, glucuronate and sulfate conjugates by the MRP gene-encoded conjugate export pump. Cancer Res, 56:988–994, 1996.PubMedGoogle Scholar
  48. 48.
    Rappa G, Finch RA, Sartorelli AC, Lorico A. New insights into the biology and pharmacology of the multidrug resistance protein (MRP) from gene knockout models. Biochem Pharmacol, 58:557–562, 1999.PubMedCrossRefGoogle Scholar
  49. 49.
    Dulik DM, Fenselau C, Hilton J. Characterization of melphalan-glutathione adducts whose formation is catalysed by glutathione S-transferases. Biochem Pharmacol, 35:3404–3409, 1986.CrossRefGoogle Scholar
  50. 50.
    Zhang K, Wong KP. Glutathione conjugation of chlorambucil: measurement and modulation by plant polyphenols. Biochem J, 325:417–422, 1997.PubMedGoogle Scholar
  51. 51.
    Gamcsik MP, Hamill TG, Colvin OM. NMR studies of conjugation of mechlorethamine with glutathione. J Med Chem, 33:1009–1014, 1990.PubMedCrossRefGoogle Scholar
  52. 52.
    Dirven HA, Megens I, Oudshoorn MJet at.Glutathione conjugation of cytostatic drug ifosfamide and the role of human glutathione S-transferases. Chem Res Toxicol, 8:979–986, 1995.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang K, Mack P, Wong K.P. Glutathione-related mechanisms in cellular resistance to anticancer drugs (review). Int J Oncol, 12:871–882, 1998.PubMedGoogle Scholar
  54. 54.
    Kotoh S, Naito S, Yokomizo Aet al.Enhanced expression of y-glutamylcysteine synthetase and glutathione S-transferase genes in cisplatin-resistant bladder cancer cells with multidrug resistance phenotype. J Urol, 157:1054–1058, 1997.PubMedCrossRefGoogle Scholar
  55. 55.
    Saburi Y, Nakagawa M, Ono Met al.Increased expression of glutathione S-transferase gene in cis-diamminedichloroplatinum(II)-resistant variants of a Chinese hamster ovary cell line. Cancer Res, 49:7020–7025, 1989.PubMedGoogle Scholar
  56. 56.
    Goto S, lida T, Oka Met al.Overexpression of glutathione S-transferase 7C enhances the adduct formation of cisplatin with glutathione in human cancer cells. Free Radic Res, 31:549–558, 1999.PubMedCrossRefGoogle Scholar
  57. 57.
    Ban N, Takahashi Y, Takayama Tet al.Transfection of glutathione 5-transferase (GST)-it antisense complimentary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan and etoposide. Cancer Res, 56:3577–3582, 1996.PubMedGoogle Scholar
  58. 58.
    Nakagawa K, Saijo N, Tsuchida Set al.Glutathione S-transferase IL as a determinant of drug resistance in transfectant cell lines. J Biol Chem, 265:4296–4301, 1990.PubMedGoogle Scholar
  59. 59.
    Moscow JA, Townsend AJ, Cowan KH. Elevation of rc class glutathione S-transferase activity in human breast cancer cells by transfection of the GST:ir gene and its effect to sensitivity to toxins. Mol Pharmacol, 36:22–28, 1989.PubMedGoogle Scholar
  60. 60.
    Schecter RL, Alaoui-Jamali M, Woo Aet al.Expression of a rat glutathione Stransferase complimentary DNA in rat mammary carcinoma cells: impact upon alkylator-induced toxicity. Cancer Res, 53:4900–4906, 1993.PubMedGoogle Scholar
  61. 61.
    Greenbaum M, Letourneau S, Assar Het a/. Retrovirus-mediated gene transfer of rat glutathione 5-transferase Yc confers alkylating drug resistance in NIH 3T3 mouse fibroblasts. Cancer Res, 54:4442–4447, 1994.PubMedGoogle Scholar
  62. 62.
    Doroshow JH, Metz MZ, Matsumoto Let al.Transduction of NIH 3T3 cells with a retrovirus carrying both human MDRI and glutathione S-transferase it produces broad-range multidrug resistance. Cancer Res, 55:4073–4078, 1995.PubMedGoogle Scholar
  63. 63.
    Godwin AK, Meister A, O’Dwyer PJet al.High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Pro Natl Acad Sci USA, 89:3070–3074, 1992.CrossRefGoogle Scholar
  64. 64.
    Yao XS, Godwin AK, Johnson SWet al.Evidence for altered regulation of yglutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatinresistant human ovarian cancer cell lines. Cancer Res, 55:4367–4374, 1995.PubMedGoogle Scholar
  65. 65.
    Mulcahy RT, Untawale S, Gipp JJ. Transcriptional up-regulation of y-glutamylcysteine synthetase gene expression in melphalan-resistant human prostate carcinoma cells. Mol Pharmacol, 46:909–914, 1994.PubMedGoogle Scholar
  66. 66.
    Iida T, Mori K, Goto Set al.Co-expression of gamma-glutamylcysteine synthetase subunits in response to cisplatin and doxorubicin in human cancer cells. Int J Canc, 82:405–411, 1999.CrossRefGoogle Scholar
  67. 67.
    Mulcahy RT, Bailey IIH, Gipp JJ. Transfection of complimentary DNAs for the heavy and light subunits of human y-glutamylcysteine synthetase results in an elevation of intracellular glutathione and resistance to melphalan. Cancer Res, 55:4771–4775, 1995.PubMedGoogle Scholar
  68. 68.
    Kurokawa H, Ishida T, Nishio Ket al.y-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione Sconjugate export pump and cisplatin resistance. Biochem Biophys Res Commun, 216:258–264, 1995.PubMedCrossRefGoogle Scholar
  69. 69.
    Ishikawa T, Bao J-J, Yamane Yet al.Coordinated induction of MRP-GS-X pump and yglutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem, 271:14981–14988, 1996.PubMedCrossRefGoogle Scholar
  70. 70.
    Ishikawa T, Wright CD, Ishizuka H. GS-X pump is functionally overexpressed in cisdaimminechloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. J Biol Chem, 269:29085–29093, 1994.PubMedGoogle Scholar
  71. 71.
    Kuo MT, Bao JJ, Curley SAet al.Frequent co-ordinated overexpression of the MRP/GS-X pump and y-glutamylcysteine synthetase genes in human colorectal cancers. Cancer Res, 56:3642–3644, 1996.PubMedGoogle Scholar
  72. 72.
    Ogretmen B, Bahadori H, McCauley MDet al.Co-ordinated over-expression of the MRP and y-glutamylcysteine synthetase genes, but not MDR1, correlates with doxorubicin resistance in human malignant mesothelioma cell lines. Int J Cancer, 75:757–761, 1998.PubMedCrossRefGoogle Scholar
  73. 73.
    Morrow CS, Smitherman PK, Diah SKet al.Coordinated action of glutathione Stransferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification. J Biol Chem, 273:20114–20120, 1998.PubMedCrossRefGoogle Scholar
  74. 74.
    Zaman GJR, Lankelma J, Tellingen 0et al.Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. PNAS USA, 92:7690–7694, 1995.PubMedCrossRefGoogle Scholar
  75. 75.
    Griffith OW. Mechanisms of action, metabolism and toxicity of butathionine sulfoximine and its higher homologues; potent inhibitors of glutathione biosynthesis. J Biol Chem, 257:13704–13708, 1982.PubMedGoogle Scholar
  76. 76.
    Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med, 27:922–935, 1999.PubMedCrossRefGoogle Scholar
  77. 77.
    Griffith OW, Mulcahy RT. The enzymes of glutathione synthesis: y-glutamylcysteine synthetase. In: Advances in Enzymology and Related Areas of Molecular Biology, Volume 73: Mechanism of Enzyme Action, Part A, D Purich (ed.), John Wiley and Sons, New York, NY, 1999.Google Scholar
  78. 78.
    Kramer RA, Greene K, Ahmad S, Vistica DT. Chemosensitization of L-phenylalanine mustard by the thiol-modulating agent buthionine sulfoximine. Cancer Res, 47:1593–1597, 1987.PubMedGoogle Scholar
  79. 79.
    O’Dwyer PJ, Hamilton TC, LaCreta FPet al.Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J Clin Oncol, 14:249–256, 1996.PubMedGoogle Scholar
  80. 80.
    Bailey HH, Mulcahy RT, Tutsch KDet al.Phase I clinical trial of intravenous Lbuthionine sulfoximine and melphalan: an attempt at modulation of glutathione. J Clin Oncol, 12:194–205, 1994.PubMedGoogle Scholar
  81. 81.
    Bailey HH, RippleGTutsch KDet al. Phase I study of continuous-infusion L-S,Rbuthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst, 89:1789–1796, 1997.PubMedCrossRefGoogle Scholar
  82. 82.
    O’Dwyer PJ, Hamilton TC, Young RCet al.Depletion of glutathione in normal and malignant human cells in vivo by butathionine sulfoximine: clinical and biochemical results. J Natl Cancer Instit, 84:264–267, 1992.CrossRefGoogle Scholar
  83. 83.
    Hamilton TC, Lai GM, Rothenberg ML. Mechanisms of resistance to alkylating agents and cisplatin. In:Cancer Treatment and Research: Drug Resistance, RF Ozols (ed.), Martinus Nijhoff, Boston, MA, 1989.Google Scholar
  84. 84.
    Batist G, Schecter RL, Karp Wet al.Effects of BSO infusion on GSH and related proteins in patients with metastatic melanoma. Submitted.Google Scholar
  85. 85.
    Meister A. Glutathione deficiency produced by inhibition of its synthesis and its reversal; applications in research and therapy. Pharmacol Ther, 51:155–194, 1991.PubMedCrossRefGoogle Scholar
  86. 86.
    Anderson ME, Luo J-L. Glutathione therapy: from prodrugs to genes. Sem Liver Dis, 18:415–424, 1998.CrossRefGoogle Scholar
  87. 87.
    Russo A, Mitchell JB, McPherson SJ, Friedman N. Alteration of bleomycin cytotoxicity by glutathione depletion or elevation. Int J Radiat Oncol Biol Phys, 10:1675–1678, 1983.CrossRefGoogle Scholar
  88. 88.
    Russo A, De Graff W, Friedman N, Mitchell JB. Selective modulation of glutathione levels in human normal versus tumor cells and subsequent differential response to chemotherapy drugs. Cancer Res, 46:2845–2848, 1986.PubMedGoogle Scholar
  89. 89.
    Wang T, Chen X, Schecter Ret al.Modulation of glutathione by a cysteine pro-drug enhances in vivo tumor response. J Pharm Exp Ther, 276:1169–1173, 1996.Google Scholar
  90. 90.
    Baruchel S, Wang T, Farah Ret al.In vivo selective modulation of tissue glutathione in a rat mammary carcinoma model. Biochem Pharmacol, 50:1499–1502, 1995.CrossRefGoogle Scholar
  91. 91.
    Chen X, Batist G. Sensitization effect of L-2-oxothiazolidine-4-carboxylate on tumor cells to melphalan and the role of 5-oxo-l-prolinase in glutathione modulation in tumor cells. Biochem Pharm, 56:743–749, 1998.PubMedCrossRefGoogle Scholar
  92. 92.
    Wellner VP, Anderson ME, Puri RNet al.Radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts. Pro Natl Acad Sci USA, 81:4732–4735, 1984.CrossRefGoogle Scholar
  93. 93.
    Benson AB. Oltipraz: a laboratory and clinical review. J Cell Biochem, 17F:278–291, 1993.CrossRefGoogle Scholar
  94. 94.
    DCPC Chemoprevention Branch agents under evaluation. September 1990. Prepared under NCI contract NO1-CN-95159–03.Google Scholar
  95. 95.
    Langouet S, Macheo K, Berthou Fet al.Effects of administration of the chemoprotective agent oltipraz on CYP1A and CYP2B in rat liver and rat hepatocytes in culture. Carcinogenesis, 18:1343–1349, 1997.PubMedCrossRefGoogle Scholar
  96. 96.
    Jaitovitch-Groisman I, Fotouhi-Ardakani N, Schecter Ret al.Modulation of glutathione s-transferase alpha by hepatitis B virus and the chemopreventive drug oltipraz. J Biol Chem, 275:33395–33403, 2000.PubMedCrossRefGoogle Scholar
  97. 97.
    Ciaccio PJ, Shen H, Kruh GD, Tew KD. Effects of chronic ethacrynic acid exposure on glutathione conjugation and MRP expression in human colon tumor cells. Biochem Biophys Res Commun, 222:111–115, 1996.PubMedCrossRefGoogle Scholar
  98. 98.
    Ahokas JT, Nicholls FA, Ravenscroft PJ, Emmerson PJ. Inhibition of purified rat liver glutathione S-transferase isozymes by diuretic drugs. Biochem Pharmacol, 34:2157–2161, 1990.CrossRefGoogle Scholar
  99. 99.
    Ploemen J, van Ommen B, van Bladeren PJ. Inhibition of rat and human glutathione Stransferase isoenzymes by ethacrynic acid and its glutathione conjugate. Biochem Pharmacol, 40:1631–1635, 1990.PubMedCrossRefGoogle Scholar
  100. 100.
    Nagourney RA, Messenger JC, Kern DH, Weisenthal LM. Enhancement of anthracycline and alkylator cytotoxicity by ethacrynic acid in primary cultures of human tissues. Cancer Chemother Pharmacol, 26:318–322, 1990.PubMedCrossRefGoogle Scholar
  101. 101.
    Hansson J, Berhane K, Castro VMet al.Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid. Cancer Res, 51:94–98, 1991.PubMedGoogle Scholar
  102. 102.
    Xu BH, Singh SV. Effect of buthionine sulfoximine and ethacrynic acid on cytotoxic activity of mitomycin C analogues BMY 25282 and BMY 25067. Cancer Res, 52:6666–6670, 1992.PubMedGoogle Scholar
  103. 103.
    Tew KD, Bomber AM, Hoffman SJ. Ethacrynic acid and piripost as enhancers of cytotoxicity in drug resistant and sensitive cell lines. Cancer Res, 48:3622–3625, 1988.PubMedGoogle Scholar
  104. 104.
    Kuzmich S, Vanderveer LA, Walsh ESet al.Increased levels of glutathione Stransferase IC transcript as a mechanism of resistance to ethacrynic acid. Biochem J, 269:47–54, 1992.Google Scholar
  105. 105.
    O’Dwyer PJ, LaCreta F, Nash Set al.Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res, 51:6059–6065, 1991.PubMedGoogle Scholar
  106. 106.
    Wijnholds J, Evers R, van Leusden MRet al.Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med, 3:1275–1279, 1997.PubMedCrossRefGoogle Scholar
  107. 107.
    Ford JM and Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer. Phamacol Rev, 42:155–199, 1990.Google Scholar
  108. 108.
    Barrand MA, Rhodes T, Center MSet al.Chemosensitization and drug accumulation effects of cyclosporin A, PSC 833 and verapamil in human MDR large cell lung cancer cells expressing a 190k membrance protein distinct from P-glycoprotein. Eur J Cancer, 29A:408–415, 1993.PubMedCrossRefGoogle Scholar
  109. 109.
    Leier I, Jedlitschky G, Buchholz Uet al.The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related compounds. J Biol Chem, 269:27807–27810, 1994.PubMedGoogle Scholar
  110. 110.
    Gekeler V, Ise W, Sanders KHet al.The leukotriene LTD4receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. Biochem Biophys Res Commun, 208:345–352, 1995.PubMedCrossRefGoogle Scholar
  111. 111.
    Endo K, Maehara Y, Ichiyashi Yet al.Multidrug resistance-associated protein expression in clinical gastric carcinoma. Cancer, 7:1681–1687, 1996.Google Scholar
  112. 112.
    Laird DW, Fistouris P, Batist Get al.Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer Res, 59:4104–4110, 1999.PubMedGoogle Scholar
  113. 113.
    Oskar S, Frankhurt D, Sugarbaker EV. Intercellular transfer of drug resistance. Cancer Res, 51:1190–1195, 1991.Google Scholar
  114. 114.
    Carystinos GD, Alaoui-Jamali MA, Phipps Jet al.Up-regulation of gap junctional intercellular communication and connexin 43 expression by cyclic-AMP and all-transretinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells. Cancer Chemother Pharmacol, 47:126–132, 2001.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • David Hamilton
    • 1
  • Nasser Fotouhi-Ardakani
    • 2
  • Gerald Batist
    • 3
  1. 1.Department of Pharmacology and TherapeuticsMcGill University and Lady Davis Institute for Medical Research, Sir Mortimer B Davis-Jewish General HospitalMontreal, QuebecCanada
  2. 2.Department of Experimental MedicineMcGill University and Lady Davis Institute for Medical Research, Sir Mortimer B Davis-Jewish General HospitalMontreal, QuebecCanada
  3. 3.The Center for Translational Research in CancerMcGill University and Lady Davis Institute for Medical Research, Sir Mortimer B Davis-Jewish General HospitalMontreal, QuebecCanada

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