, Volume 12, Issue 1–3, pp 155–170 | Cite as

Glutathione-related enzymes, glutathione and multidrug resistance

  • Jeffrey A. Moscow
  • Katharine H. Dixon


This review examines the hypothesis that glutathione and its associated enzymes contribute to the overall drug-resistance seen in multidrug resistant cell lines. Reports of 34 cell lines independently selected for resistance to MDR drugs are compared for evidence of consistent changes in activity of glutathione-related enzymes as well as for changes in glutathione content. The role of glutathione S-transferases in MDR is further analyzed by comparing changes in sensitivity to MDR drugs in cell lines selected for resistance to non-MDR drugs that have resulting increases in glutathione S-transferase activity. In addition, results of studies in which genes for glutathione S-transferase isozymes were transfected into drug-sensitive cells are reviewed. The role of the glutathione redox cycle is examined by comparing changes in elements of this cycle in MDR cell lines as well as by analyzing reports of the effects of glutathione depletion on MDR drug sensitivity. Overall, there is no consistent or compelling evidence that glutathione and its associated enzymes augment resistance in multidrug resistant cell lines.

Key words

etoposide doxorubucin glutathione glutathione peroxidase glutathione reductase glutathione S-transferase multidrug resistance P-glycoprotein vincristine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Batist G, Tulpule A, Sinha BK, Katki AG, Myers CE and Cowan KH (1986) Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. J Biol Chem 261: 15544–15549.Google Scholar
  2. 2.
    Cowan KH, Batist G, Tulpule A, Sinha BK and Myers CE (1986) Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. Proc Natl Acad Sci USA 83: 9328–9332.Google Scholar
  3. 3.
    Mannervik B, Awasthi YC, Board PG, Hayes JD, Di Ilio C, Ketterer B, Listowsky I, Morgenstern R, Muramatsu M, Pearson W, Pickett CB, Sato K, Widersten M and Wolf CR (1992) Nomenclature for glutathione transferases. Biochem J 282: 305–308.Google Scholar
  4. 4.
    Wolf CR, Macpherson JS and Smyth JF (1986) Evidence for the metabolism of mitoxantrone by microsomal glutathione transferases and 3-methylcholanthrene-inducible glucuronosyl transferases. Biochem Pharmacol 35: 1577–1581.Google Scholar
  5. 5.
    Ciaccio PJ, Tew KD and LaCreta FP (1990) The spontaneous and glutathione S-transferase-mediated reaction of chlorambucil with glutathione. Cancer Commun 2: 279–285.Google Scholar
  6. 6.
    Meyer PJ, Gilmore KS, Harris JM, Hartley JA and Ketterer B (1992) Chlorambucil/monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases. Br J Cancer 66: 433–438.Google Scholar
  7. 7.
    Dulik DM, Fenselau C and Hilton J (1986) Characterization of melphalan-glutathione adducts whose formation is catalyzed by glutathione transferases. Biochem Pharmacol 35: 3405–3409.Google Scholar
  8. 8.
    Berhane K and Mannervik B (1990) Inactivation of the genotoxic aldehyde acrolein by human glutathione transferases of classes alpha, mu and pi. Mol Pharmac 37: 251–254.Google Scholar
  9. 9.
    Ketterer B, Meyer DJ and Clark AG (1988) Soluble glutathione transferase isozymes. In: Ketterer B and Seis H (Eds) Glintathione Conjugation: Mechanisms and Biological Significance (pp. 74–137), London, Academic Press.Google Scholar
  10. 10.
    Arias IM (1979) Ligandin: review and update of a multifunctional protein. Medical Biology 57: 328–334.Google Scholar
  11. 11.
    Fairchild CR, Moscow JA, O'Brien EE and Cowan KH (1990) Multidrug resistance in cells transfected with human genes encoding a variant P-glycoprotein and glutathione S-transferase-pi. Mol Pharmacol 37: 801–809.Google Scholar
  12. 12.
    Black SM, Beggs JD, Hayes JD, Bartoszek A, Muramatsu M, Sakai M and Wolf CR (1990) Expression of human glutathione S-transferases inSaccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil. Biochem J 268: 309–315.Google Scholar
  13. 13.
    Sinha BK, Mimnaugh EG, Rajagopalan S and Myers CE (1989) Adriamycin activation and oxygen free radical formation in human breast tumor cells: Protective role of glutathione peroxidase in adriamycin resistance. Cancer Res 49: 3844–3848.Google Scholar
  14. 14.
    Moscow JA, Townsend AJ and Cowan KH (1989) Elevation of pi class glutathione S-transferase activity in human breast cancer cells by transfection of the GST pi gene and its effect on sensitivity to toxins. Mol Pharmacol 36: 22–28.Google Scholar
  15. 15.
    Medh RD, Gupta V, Zhang Y, Awasthi YC and Belli JA (1990) Glutathione S-transferase and P-glycoprotein in multidrug resistant Chinese hamster cells. Biochem Pharmacol 39: 1641–1645.Google Scholar
  16. 16.
    Hoban PR, Robson CN, Davies SM, Hall AG, Cattan AR, Hickson ID and Harris AL (1992) Reduced topoisomerase II and elevated α-class glutathione S-transferase expression in a multidrug resistant CHO cell line highly cross-resistant to mitomycin C. Biochem Pharmac 43: 685–693.Google Scholar
  17. 17.
    Broxterman HJ, Pinedo HM, Kuiper CM, Schuurhuis GJ and Lankelma J (1989) Glycolysis in P-glycoprotein-overexpressing human tumor cell lines. Effects of resistance-modifying agents. Febs Lett. 247: 405–410.Google Scholar
  18. 18.
    Hamilton TC, Winker MA, Louie KG, Batist G, Behrens BC, Tsuruo T, Grotzinger KR, McKoy WM, Young RC and Ozols RF (1985) Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and-sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol 34: 2583–2586.Google Scholar
  19. 19.
    Yusa H, Hamada H and Tsuruo T (1988) Comparison of glutathione S-transferase activity between drug-resistant and-sensitive human tumor cells: Is glutathione S-transferase associated with multidrug resistance? Cancer Chemother Pharmac 22: 17–20.Google Scholar
  20. 20.
    Hosking LK, Whelan RDH, Shellard SA, Bedford P and Hill BT (1990) An evaluation of the role of glutathione and its associated enzymes in the expression of differential sensitivities to antitumor agents shown by a range of human tumour cell lines. Biochem Pharmac 40: 1833–1842.Google Scholar
  21. 21.
    Chen Y-N, Mickley LA, Schwartz AM, Acton EM, Hwang J and Fojo AT (1990) Characterization of adriamycin-resistant human breast cancer cells which display over-expression of a novel resistance-related membrane protein. J Biol Chem 265: 10073–10080.Google Scholar
  22. 22.
    Whelan RDH, Hosking LK, Townsend AJ, Cowan KH and Hill BT (1989) Differential increases in glutathione S-transferase activities in a range of multidrug-resistant human tumor cell lines. Cancer Commun 1: 359–365.Google Scholar
  23. 23.
    Yeh GC, Lopaczynska J, Poore CM and Phang JM (1992) A new functional role for P-glycoprotein: efflux pump for benzo(a)pyrene in human breast cancer MCF-7 cells. Cancer Res 52: 6692–6695.Google Scholar
  24. 24.
    Cole SP, Downes HF, Mirski SE and Clements DJ (1990) Alterations in glutathione and glutathione-related enzymes in a multidrug-resistant small cell lung cancer cell line. Mol Pharmac 37: 192–197.Google Scholar
  25. 25.
    Bellamy WT, Dalton WS, Meltzer P and Dorr RT (1989) Role of glutathione and its associated enzymes in multidrug-resistant human myeloma cells. Biochem Pharmac 38: 787–793.Google Scholar
  26. 26.
    Kramer RA, Zakher J and Kim G (1988) Role of the glutathione redox cycle in acquired and de novo multidrug resistance. Science 241: 694–697.Google Scholar
  27. 27.
    Deffie AM, Alam T, Seneviratne C, Beenken SW, Batra JK, Shea TC, Henner WD and Goldenberg GJ (1988) Multifactorial resistance to adriamycin: relationship of DNA repair, glutathione transferase activity, drug efflux, and P-glycoprotein in cloned cell lines of adriamycin-sensitive and-resistant P388 leukemia. Cancer Res 48: 3595–3602.Google Scholar
  28. 28.
    Lutzky J, Astor MB, Taub RN, Baker MA, Bhalla K, Gervasoni JJ, Rosado M, Stewart V, Krishna S and Hindenburg AA (1989) Role of glutathione and glutathione-dependent enzymes in anthracycline-resistant HL60/AR cells. Cancer Res 49: 4120–4125.Google Scholar
  29. 29.
    Kato S, Ideguchi H, Muta K, Nishimura J and Nawata H (1990) Mechanisms involved in the development of Adriamycin resistance in human leukemic cells. Leuk Res 14: 567–573.Google Scholar
  30. 30.
    Schisselbauer JC, Crescimanno M, D'Alessandro N, Clapper M, Toulmond S, Tapiero H and Tew KD (1989) Glutathione, glutathione S-transferases, and related redox enzymes in adriamycin-resistant cell lines with a multidrug resistant phenotype. Cancer Commun 1: 133–139.Google Scholar
  31. 31.
    Lai G-M, Moscow JA, Alvarez MG, Fojo AT and Bates SE (1991) Contribution of glutathione and glutathione-dependent enzymes in thereversal of adriamycin resistance in colon carcinoma cell lines. Int J Cancer 49: 688–695.Google Scholar
  32. 32.
    Chao CCK, Huan Y-T, Ma CM, Chou W-Y and Lin-Chao S (1992) Overexpression of glutathione S-transferase and elevation of thiol pools in a multidrug-resistant human colon carcinoma cell line. Mol Pharmacol 41: 69–75.Google Scholar
  33. 33.
    Whelan RDH, Waring CJ, Wolfe CR, Hayes JD, Hosking LK and Hill BT (1992) Overexpression of P-glycoprotein and glutathione S-transferase pi in MCF-7 cells selected for vincristine resistance in vitro. Int J Cancer 52: 241–246.Google Scholar
  34. 34.
    Taylor CW, Dalton WS, Parrish PR, Gleason MC, Bellamy WT, Thompson FH, Roe DJ and Trent JM (1991) Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF-7 human breast cancer cell line. Br J Cancer 63: 923–929.Google Scholar
  35. 35.
    Nair S, Singh SV, Samy TSA and Krishan A (1990) Anthracycline resistance in murine leukemic P388 cells. Biochem Pharmacol 39: 723–728.Google Scholar
  36. 36.
    Peters WHM and Roelofs HMJ (1992) Biochemical characterization of resistance to mitoxantrone and adriamycin in Caco-2 human colon adenocarcinoma cells: A possible role for glutathione S-transferases. Cancer Res 52: 1886–1890.Google Scholar
  37. 37.
    Carmichael J, Mitchell JB, Friedman N, Gazdar AF and Russo A (1988) Glutathione and related enzyme activity in human lung cancer cell lines. Br J Cancer 58: 437–440.Google Scholar
  38. 38.
    Keith WN, Stallard S and Brown R (1990) Expression ofmdr-1 and GSTπ in human breast tumours: Comparison to in vitro chemosensitivity. Br J Cancer 61: 712–716.Google Scholar
  39. 39.
    Kuroda H, Sugimoto T, Ueda K, Tsuchida S, Hori Y, Inazawa J, Sato K and Sawada T (1991) Different drug sensitivity in two neuroblastoma cell lines established from the same patient before and after chemotherapy. Int J Cancer 47: 732–737.Google Scholar
  40. 40.
    de Vries EGE, Meijer C, Timmer-Bosscha H, Berendsen HH, de Leij L and Mulder NH (1989) Resistance mechanisms in three human small cell lung cancer cell lines established from one patient during clinical follow-up. Cancer Res 49: 4175–4178.Google Scholar
  41. 41.
    Wang YY, Teicher BA, Shea TC, Holden SA, Rosbe KW, al AA and Henner WD (1989) Cross-resistance and glutathione-S-transferase-pi levels among four human melanoma cell lines selected for alkylating agent resistance. Cancer Res 49: 6185–6192. PLS CHECK NAMES!Google Scholar
  42. 42.
    Saburi Y, Nakagawa M, Ono M, Sakai M, Muramatsu M, Kohno K and Kuwano M (1989) Increased expression of glutathione S-transferase gene in cis-diamminedichloro-platinum(II) resistant variants of a Chinese hamster ovary cell line. Cancer Res 49: 7020–7025.Google Scholar
  43. 43.
    Kasahara K, Fujiwara Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K, Matsuda T and Saijo N (1991) Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Res 51: 3237–3242.Google Scholar
  44. 44.
    Shellard SA, Hosking LK and Hill BT (1991) Anomalous relationship between cisplatin sensitivity and the formation and removal of platinum-DNA adducts in two human ovarian carcinoma cell lines in vitro. Cancer Res. 51: 4557–4564.Google Scholar
  45. 45.
    Townsend AJ, Tu C-PD and Cowan KH (1991) Expression of human μ or α class glutathione S-transferases in stably transfected human MCF-7 breast cancer cells: effect on cellular sensitivity to cytotoxic agents. Mol Pharmacol 41: 230–236.Google Scholar
  46. 46.
    Leyland-Jones BR, Townsend AJ, Tu C-PD, Cowan KH and Goldsmith ME (1991) Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. Cancer Res 51: 587–594.Google Scholar
  47. 47.
    Ferguson PJ and Cheng YC (1989) Phenotypic instability of drug sensitivity in a human colon carcinoma cell line. Cancer Res 49: 1148–1153.Google Scholar
  48. 48.
    Lavoie L, Tremblay A and Mirault M-E (1992) Distinct oxido-resistance phenotype of human T47D cells transfected by rat glutathione S-transferase Yc expression vectors. J Biol Chem 267: 3632–3636.Google Scholar
  49. 49.
    Nakagawa K, Saijo N, Tsuchida S, Sakai M, Tsunokawa Y, Yokota J, Muramatsu M, Sato K, Terada M and Tew KD (1990) Glutathione-S-transferase pi as a determinant of drug resistance in transfectant cell lines. J Biol Chem 265: 4296–4301.Google Scholar
  50. 50.
    Miyazaki M, Kohno K, Saburi Y, Matsuo K, Ono M, Kuwano M, Tsuchida S, Sato K, Sakai M and Muramatsu M (1990) Drug resistance to cis-diamminedichloroplatinum (II) in Chinese hamster ovary cell lines transfected with glutathione S-transferase pi gene. Biochem Biophys Res Commun 166: 1358–1364.Google Scholar
  51. 51.
    Puchalski RB and Fahl WE (1990) Expression of recombinant glutathione S-transferase pi, Ya, or Yb1 confers resistance to alkylating agents. Proc Natl Acad Sci USA 87: 2443–2447.Google Scholar
  52. 52.
    Shea TC, Kelley SL and Henner WD (1988) Identification of an anionic form of glutathione transferase present in many human tumors and human tumor cell lines. Cancer Res 48: 527–533.Google Scholar
  53. 53.
    Moscow JA, Fairchild CR, Madden MJ, Ransom DT, Wieand HS, O'Brien EE, Poplack DG, Cossman J, Myers CE and Cowan KH (1989) Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res 49: 1422–1428.Google Scholar
  54. 54.
    di Ilio C, Sacchetta P, Del Boccio G, La Rovere G and Federici G (1985) Glutathione peroxidase, glutathione S-transferase and glutathione reductase activities in normal and neoplastic human breast tumors. Cancer Lett 29: 37–42.Google Scholar
  55. 55.
    Peters WHM, Wormskamp NGM and Thies E (1990) Expression of glutathione S-transferases in normal gastric mucosa and in gastric tumors. Carcinogenesis 11: 1593–1596.Google Scholar
  56. 56.
    Howie AF, Forrester LM, Glancey MJ, Sclager JJ, Powis G, Beckett GJ, Hayes JD and Wolf CR (1990) Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues. Carcinogenesis 11: 451–458.Google Scholar
  57. 57.
    Moorghen M, Cairns J, Forrester LM, Hayes JD, Hall A, Cattan AR, Wolf CR and Harris AL (1991) Enhanced expression of glutathione S-transferases in colorectal carcinoma compared to nonneoplastic mucosa. Carcinogenesis 12: 13–17.Google Scholar
  58. 58.
    Kodate C, Fukushi A, Narita T, Kudo K, Soma Y and Sato K (1986) Human placental form of glutathione S-transferase (GSTπ) as a new immunohistochemical marker for human colonic carcinoma. Jpn J Cancer Res 77: 226–229.Google Scholar
  59. 59.
    Tsutsume M, Sugisake T, Makino T et al. (1987) Oncofetal expression of glutathione S-transferase placental form in human stomach carcinomas. Jpn J Cancer Res 78: 631–633.Google Scholar
  60. 60.
    Peters WHM, Boon CEW, Roelofs HMJ, Wobbes T, Nagengast FM and Kemers PG (1992) Expression of drug-metabolizing enzymes and P-170 glycoprotein in colorectal carcinoma and normal mucosa. Gastroenterology 103: 448–455.Google Scholar
  61. 61.
    Carmichael J, Forrester LM, Lewis AD, Hayes JD and Wolf CR (1988) Glutathione S-transferase isozymes and glutathione peroxidase activity in normal and tumour samples from human lung. Carcinogenesis 9: 1617–1621.Google Scholar
  62. 62.
    Volm M, Mattern J and Samsel B (1992) Relationship of inherent resistance to doxorubicin, proliferative activity and expression of P-glycoprotein 170, and glutathione S-transferase π in human lung tumors. Cancer 70: 764–769.Google Scholar
  63. 63.
    Efferth T, Mattern J and Volm M (1992) Immunohistochemical detection of P-glycoprotein, glutathione S-transferase and DNA topoisomerase II in human tumors. Oncology 49: 368–375.Google Scholar
  64. 64.
    Holmes J, Wareing C, Jacobs A, Hates JD, Padua RA and Wolf CR (1990) Glutathione-S-transferase pi expression in leukaemia: A comparative analysis withmdr-1 data. Br J Cancer 62: 209–212.Google Scholar
  65. 65.
    Gekeler V, Frese G, Noller A, Handgretinger R, Wilisch A, Schmidt H, Muller CP, Dopfer R, Klingebiel T, Diddens H, Probst H and Niethammer D (1992)Mdr-1/P-glycoprotein, topoisomerase and glutathione-S-transferase π gene expression in primary and relapse state adult and childhood leukaemias. Br J Cancer 66: 507–517.Google Scholar
  66. 66.
    Cheng A-L, Su I-J, Chen Y-C, Lee T-C and Wang C-H (1993) Expression of P-glycoprotein and glutathione S-transferase in recurrent lymphoma: the possible role of Epstein-Barr virus, and other predisposing factors. J Clin Oncol 11: 109–115.Google Scholar
  67. 67.
    Satta T, Isobe K-i, Yamauchi M, Nakashima I and Takagi H (1991) Expression of MDR1 and glutathione S-transferase π genes and chemosensitivities in human gastrointestinal cancer. Cancer 69: 941–946.Google Scholar
  68. 68.
    Linsenmeyer ME, Jefferson S, Wolf M, Mattthews JP, Board PG and Woodcock DM (1992) Levels of expression of themdr-1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma. Br J Cancer 65: 471–475.Google Scholar
  69. 69.
    Koberda J and Hellman A (1991) Glutathione S-transferase activity of leukemic cells as a prognostic factor for response to chemotherapy in acute leukemias. Med Oncol Tumor Pharmacother 8: 35–38.Google Scholar
  70. 70.
    Tidefelt U, Elmhorn-Rosenborg A, Paul C, Hao X-Y, Mannervik B and Eriksson LC (1992) Expression of glutathione S-transferase π as a predictor for treatment results at different stages of acute nonlymphoblastic leukemia. Cancer Res 52: 3281–3285.Google Scholar
  71. 71.
    van der Zee AGJ, van Ommen B, Meijer C, Hollema H, van Bladeren PJ and de Vries EGE (1992) Glutathione S-transferase activity and isozyme composition in benign ovarian tumours, untreated malignant ovarian tumours, and malignant ovarian tumours after platinum/cyclophosphamide chemotherapy. Br J Cancer 66: 930–936.Google Scholar
  72. 72.
    Murphy D, McGown AT, Hall A, Cattan A, Crowther D and Fox BW (1992) Glutathione S-transferase activity and isozyme distribution in ovarian tumour biopsies taken before or after cytotoxic chemotherapy. Br J Cancer 66: 937–942.Google Scholar
  73. 73.
    Moscow JA, Townsend AJ, Goldsmith ME, Whang PJ, Vickers PJ, Poisson R, Legault PS, Myers CE and Cowan KH (1988) Isolation of the human anionic glutathione S-transferase cDNA and the relation of its gene expression to estrogen-receptor content in primary breast cancer. Proc Natl Acad Sci USA 85: 6518–6522.Google Scholar
  74. 74.
    Howie AF, Miller WR, Hawkins RA, Hutchinson AR and Beckett GJ (1989) Expression of glutathione S-transferase B1, B2, Mu and Pi in breast cancers and their relationship to oestrogen receptor status. Br J Cancer 60: 834–837.Google Scholar
  75. 75.
    Gilbert L, Elwood L, Merino M, Masood S, Barnes R, Steinberg S, Lazarus D, Pierce L, d'Angelo T, Moscow JA, Townsend AJ and Cowan KH (1993) A pilot study of Pi-class glutathione S-transferase (GSTπ) in breast cancer: Correlation with estrogen receptor expression and prognosis in node-negative breast cancer. J Clin Oncol 11: 49–58.Google Scholar
  76. 76.
    Wright C, Cairns J, Cantwell BJ, Cattan AR, Hall AG, Harris AL and Horne CHW (1992) Response to mitoxantrone in advanced breast cancer: Correlation with expression of c-erbB-2 protein and glutathione S-transferases. Br J Cancer 65: 271–274.Google Scholar
  77. 77.
    Toffoli G, Frustaci S, Tumiotto L, Talamini R, Gherlinzoni F, Picci P and Boiocchi (1992) Expression of MDR1 and GSTπ in human soft tissue sarcomas: relation to drug resistance and biological aggressiveness. Ann Oncol 3: 63–69.Google Scholar
  78. 78.
    Cowan KH, Batist G, Tulpule A, Sinha BK and Myers CE (1986) Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. Proc Natl Acad Sci USA 83: 9328–9332.Google Scholar
  79. 79.
    Kitahara A, Satoh K, Nishimura K, Ishikawa T, Kazuo R, Sato K, Tsuda H and Itao N (1984) Purification, induction, and distribution of placental glutathione S-transferase: A new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis. Proc Natl Acad Sci USA 82: 3964–3968.Google Scholar
  80. 80.
    Moore MA, Nakagawa K, Satoh K, Ishikawa T and Sato K (1987) Single GST-P positive liver cells; putative initiated hepatocytes. Carcinogenesis 8: 483–486.Google Scholar
  81. 81.
    Dixon KH, Cowell IG, Xia CL, Pemble SE, Ketterer B and Taylor JB (1989) Control of expression of the human glutathione S-transferase pi gene differs from its rat orthologue. Biochem Biophys Res Commun 163: 815–822.Google Scholar
  82. 82.
    Burt RK, Garfield S, Johnson K and Thorgeirsson SS (1988) Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione S-transferase-P and increased resistance to cytotoxic chemicals. Carcinogenesis 9: 2329–2332.Google Scholar
  83. 83.
    Morrow CS, Goldsmith ME and Cowan KH (1990) Regulation of human glutathione S-transferase pi gene transcription: influence of 5′-flanking sequences and transactivating factors which recognize AP-1-binding sites. Gene 88: 215–225.Google Scholar
  84. 84.
    Morrow CS, Chiu J and Cowan KH (1992) Posttranscriptional control of glutathione S-transferase π gene expression in human breast cancer cells. J Biol Chem 267: 10544–10550.Google Scholar
  85. 85.
    Goodman J and Hochstein P (1977) Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun 77: 797–803.Google Scholar
  86. 86.
    Minmaugh EG, Trush MA, Ginsburg E and Gram TE (1982) Differential effects of anthracycline drugs on rat heart and liver microsomal reduced nicotinamide adenine diphosphate-dependent lipid peroxidation. Cancer Res 42: 3574–3582.Google Scholar
  87. 87.
    Minmaugh EG, Gram TE and Trush MA (1983) Stimulation of mouse heart and liver microsomal lipid peroxidation by anthracycline anticancer drugs: Characterization and effects of reactive oxygen scavengers. J Pharmacol Exp Ther 226: 806–816.Google Scholar
  88. 88.
    Julicher RH, Sterreberg L, Bast A, Riksen RO, Koomen JM and Noorhoek J (1986) The role of lipid peroxidation in acute doxorubicin-induced cardiotoxicity as studied in rat isolated heart. J Pharm Pharmacol 38: 277–282.Google Scholar
  89. 89.
    Minmaugh EG, Kennedy KA, Trush MA and Sinha BK (1985) Adriamycin-enhanced membrane lipid peroxidation in isolated rat nuclei. Cancer Res 45: 3296–3304.Google Scholar
  90. 90.
    Lown JW, Sim SK, Majumbar KC and Chang R (1977) Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents. Biochem Biophys Res Commun 76: 705–710.Google Scholar
  91. 91.
    Lown JW, Chen HH, Plambeck JA and Acton EM (1982) Further studies on the generation of reactive oxygen species from activated anthracyclines and the relationship to cytotoxic action and cardiotoxic effects. Biochem Pharmacol 31: 575–581.Google Scholar
  92. 92.
    Eliot H, Gianni L and Myers C (1984) Oxidative destruction of DNA by the adriamycin-iron complex. Biochemistry 23: 928–936.Google Scholar
  93. 93.
    Doroshow JH, Akman S, Chu F-F and Esworthy S (1990) Role of glutathione-glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones. Pharmacol Ther 47: 359–370.Google Scholar
  94. 94.
    Sinha BK, Katki AG, Batist G, Cowan KH and Myers CE (1987) Adriamycin-stimulated hydroxyl radical formation in human breast tumor cells. Biochem Pharmacol 36: 793–796.Google Scholar
  95. 95.
    Doroshow JH (1986) Prevention of doxorubicin-induced killing of MCF-7 human breast cancer cells by oxygen radical scavengers and iron chelating agents. Biochem Biophys Res Comm 135: 330–335.Google Scholar
  96. 96.
    Doroshow JH (1986) Role of hydrogen peroxide and hydroxyl radical formation in the killing of Ehrlich tumor cells by anticancer quinones. Proc Natl Acad Sci USA 83: 4514–4518.Google Scholar
  97. 97.
    Sinha BK, Katki AG, Batist G, Cowan KH and Myers CE (1987) Differential formation of hydroxyl radicals by Adriamycin in sensitive and resistant MCF-7 human breast tumor cells: Implications for the mechanism of action. Biochemistry 26: 3776–3781.Google Scholar
  98. 98.
    Townsend AJ, Morrow CS, Sinha BK and Cowan KH (1991) Selenium-dependent glutathione peroxidase expression is inversely related to estrogen receptor content in breast cancer. Cancer Commun 3: 265–270.Google Scholar
  99. 99.
    Keizer HG, van Rijn J, Pinedo HM and Joenje H (1988) Effect of endogenous glutathione, superoxide dismutases, catalase, and glutathione peroxidase on Adriamycin tolerance of Chinese hamster ovary cells. Cancer Res 48: 4493–4497.Google Scholar
  100. 100.
    Rosazza JPN, Duffel MW, Elmarakby S and Ahm SH (1992) Metabolism of Caranthus alkaloids: FromStreptomyces griseus to monoamine oxidase-B. J Nat Prod 55: 269.Google Scholar
  101. 101.
    Schlaifer D, Cooper MR, Attal M, Sartor AO, Trepel JB, Laurent G and Myers CE (1993) Myeloperoxidase: An enzyme involved in intrinsic vincristine resistance in human myeloblastic leukemia. Blood 81: 482–489.Google Scholar
  102. 102.
    Mullenbach GT, Tabrizi A, Irvine BD, Bell GI, Tainer JA and Hallewell RA (1988) Selenocysteine's mechanisms of incorporation and evolution revealed in cDNAs of three glutathione peroxidases. Protein Engineering 2: 239–246.Google Scholar
  103. 103.
    Sukenaga Y, Ishida K, Yakeda T and Tagaki K (1987) cDNA sequence coding for human glutathione peroxidase. Nucleic Acids Res 15: 7178.Google Scholar
  104. 104.
    Moscow JA, Morrow CS, He R, Mullenbach GT and Cowan KH (1992) Structure and function of the 5′ flanking sequence of the human cytosolic selenium-dependent glutathione peroxidase gene (hgpx1). J Biol Chem 267: 5949–5958.Google Scholar
  105. 105.
    Akasaka M, Mizoguchi J and Takahashi K (1990) A human cDNA sequence for a novel glutathione peroxidase related protein. Nucleic Acids Res 18: 4619.Google Scholar
  106. 106.
    Chu FF, Doroshow JH and Esworthy RS (1993) Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. J Biol Chem 268: 2571–2576.Google Scholar
  107. 107.
    Takahashi K, Akasak M, Yamamoto Y, Kobayashi C, Mizoguchi J and Koyama J (1990) Primary structure of human plasma glutathione peroxidase deduced from cDNA sequences. J Biochem 108: 145–148.Google Scholar
  108. 108.
    Chu FF, Esworthy RS, Doroshow JH, Doan K and Liu X-F (1992) Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung and breast in humans and rodents. Blood 79: 3233–3238.Google Scholar
  109. 109.
    Maiorino M, Chu FF, Ursini F, Davies KJA, Doroshow JH and Esworthy RS (1991) Phospholipid hydroperoxide glutathione peroxidase is the 18-kDa selenoprotein expressed in human tumor cell lines. J Biol Chem 266: 7728–7732.Google Scholar
  110. 110.
    Schuckelt R, Bigelius-Flohe R, Maiorino M, Roveri A, Reumkens J, Strassburger W, Ursini F, Wolf B and Flohe L (1991) Phospholipid hydroperoxide glutathione peroxidase is a seleno-enzyme distinct from the classical glutathione peroxidase as evident from cDNA and amino acid sequencing. Free Rad Res Commun 14: 343–361.Google Scholar
  111. 111.
    Duan YJ, Komura S, Fiszer-Szafarz D and Yagi K (1988) Purification and characterization of a novel monomeric glutathione peroxidase from rat liver. J Biol Chem 263: 19003–19008.Google Scholar
  112. 112.
    Ghyselink NB and Dufaure J-P (1990) A mouse cDNA sequence for epidydymal androgen-regulated proteins related to glutathione peroxidase. Nucleic Acids Res 18: 7144.Google Scholar
  113. 113.
    Arrick BA, Nathan CF and Cohn ZA (1983) Inhibition of glutathione synthesis augments lysis of murine tumors cells by sulfhydryl-reactive antineoplastics. J Clin Invest 71: 258–267.Google Scholar
  114. 114.
    Lee FYF, Vessey AR and Siemann DW (1988) Glutathione as a determinant of cellular response to doxorubicin. NCI Monographs 6: 211–215.Google Scholar
  115. 115.
    Russo A and Mitchell JB (1985) Potentiation and protection of doxorubicin cytotoxicity by cellular glutathione modulation. Cancer Treatment Rep 69: 1293–1296.Google Scholar
  116. 116.
    Dusre L, Mimnaugh EG, Myers CE and Sinha BK (1989) Potentiation of doxorubicin cytotoxicity by buthionine sulphoximine in multidrug-resistant human breast tumor cells. Cancer Res 49: 511–515.Google Scholar
  117. 117.
    Lau DHM, Lewis AD, Ehsan MN and Sikic BI (1991) Multifactorial mechanisms associated with broad crossresistance of ovarian carcinoma cells selected by cyanomorpholino doxorubicin. Cancer Res 51: 5181–5187.Google Scholar
  118. 118.
    Lee FYF, Sciandra J and Siemann OW (1989) A study of the mechanism of resistance to adriamycin in vivo. Glutathione metabolism, P-glycoprotein expression and drug transport. Biochem Pharmac 38: 3697–3705.Google Scholar
  119. 119.
    Rosenburg MC, Colvin OM, Griffith OW, Bigner SH, Elion GB, Horton JK, Lilley E, Bigner DB and Friedman HS (1989) Establishment of a melphalan-resistant rhabdomyosarcoma xenograft with cross resistance to vincristine and enhanced sensitivity following buthionine sulphoximine-mediated glutathione depletion. Cancer Res 49: 6917–6922.Google Scholar
  120. 120.
    Ford JM, Yang JM and Hait WM (1991) Effect of buthionine sulphoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice. Cancer Res 51: 67–72.Google Scholar
  121. 121.
    Doroshow JH, Akman S, Esworthy S, Chu F-F and Burke T (1991) Doxorubicin resistance conferred by selective enhancement of intracellular glutathione peroxidase or superoxide dismutase content in human breast cancer cells. Free Rad Res Commun 12–13: 779–781.Google Scholar
  122. 122.
    Mirault M-E, Tremblay A, Beudoin N and Tremblay M (1991) Overexpression of selenoglutathione peroxidase by gene transfer enhances the resistance of T47 human breast cancer cells to clastogenic oxidants. J Biol Chem 266: 20752–20760.Google Scholar
  123. 123.
    Hwang C, Sinskey AJ and Lodish HF (1992) Oxidized redox state of glutathione in the endoplasmic reticulum. Science 257: 1496–1502.Google Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • Jeffrey A. Moscow
    • 1
  • Katharine H. Dixon
    • 1
  1. 1.Medicine Branch, National Cancer InstituteNational Institutes of HealthBethesdaUSA

Personalised recommendations