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Activity of melphalan in combination with the glutathione transferase inhibitor sulfasalazine

  • Original Article
  • Glutathione, Glutathione Transferase, Resistance, Modulation
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Abstract

Glutathione (GSH) transferases (GST), a family of detoxification enzyme proteins, are suggested to play an important role in tumor cell resistance to melphalan. The GST-activity inhibitor ethacrynic acid has been shown to increase the antitumor activity of melphaln in vitro as well as in vivo. In this study we determined the activity and toxicity of melphalan in combination with another GST-activity inhibitor, sulfasalazine, an agent used to treat ulcerative colitis. We entered 37 previously treated patients with advanced cancer of different histologies on sulfasalazine given at the individually calculated maximum tolerated dose (MTD) and melphalan given at doses beginning at 20 mg/m2. The main toxicity arising from this combination was nausea and vomiting, whereas increased myelosuppression was not observed. A partial response was seen in 2/4 of the ovarian cancer patients only. Plasma sulfasalazine levels varied between 2.5 and 47.1 μg/ml. Although reductions in GSH/GST levels were observed in peripheral mononuclear cells of certain patients following sulfasalazine treatment, there was no correlation between the extent of reduction and the plasma sulfasalazine level. A larger patient population must be studied to determine the usefulness of this combination.

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References

  1. Ahmad H, Singhal SS, Awasthi S (1992) The inhibition of the α, μ, and π class isozymes of glutathione S-transferases by sulfasalazine, 5-aminosalicylic acid and sulfapyridine. Biochem Arch 8: 73

    Google Scholar 

  2. Armstrong DK, Gordon GB, Hilton J, Streeper RT, Colvin OM, Davidson NE (1992) Hepsulfam sensitivity in human breast cancer cell lines: the role of glutathione and glutathione S-transferase in resistance. Cancer Res 52: 1416

    Google Scholar 

  3. Arrick BA, Nathan CF (1984) Glutathione metabolism as a determinant of therapeutic efficacy: a review. Cancer Res 44: 4224

    Google Scholar 

  4. Awasthi YC, Garg HS, Dao DD, Partridge CA, Srivastava SK (1981) Enzymatic conjugation of erythrocyte glutathione with 1-chloro-2,4-dinitrobenzene: the fate of glutathione conjugate in erythrocytes and the effect of glutathione depletion on hemoglobin. Blood 58: 733

    Google Scholar 

  5. Batist G, Tulpule A, Sinha BK, Katki AG, Myers CE, Cowan KH (1986) Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. J Biol Chem 261: 15544

    Google Scholar 

  6. Bellamy WT, Dalton WS, Gleason MC, Grogan TM, Trent JM (1991) Development and characterization of a melphalan-resistant human multiple myeloma cell line. Cancer Res 51:995

    Google Scholar 

  7. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of principle of protein-dye binding. Anal Biochem 72: 248

    Google Scholar 

  8. Ciaccio PJ, Tew KD, LaCreta FP (1990) The spontaneous and glutathioneS-tranferase-mediated reaction of chlorambucil with glutathione. Cancer Commun 2: 279

    Google Scholar 

  9. Clapper ML, Hoffman SJ, Tew KD (1990) Sensitization of human colon tumor xenografts to L-phenylalanine mustard using ethacrynic acid. J Cell Pharmacol 1: 71

    Google Scholar 

  10. Das KM, Dubin R (1976) Clinical pharmacokinetics of sulphasalazine. Clin Pharmacokinet 1: 406

    Google Scholar 

  11. Dulik DM, Fenselau C, Hilton J (1986) Characterization of a melphalan-glutathione adduct whose formation is catalyzed by glutathione transferases. Biochem Pharmacol 35: 3405

    Google Scholar 

  12. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70

    Google Scholar 

  13. Fairchild CR, Cowan KH (1991) Multidrug resistance: a pleiotropic response to cytotoxic drugs. Int J Radiat Oncol Biol Phys 20: 361

    Google Scholar 

  14. Habig WH, Pabst MJ, Jakoby WB (1974) GlutathioneS-transferases: the first step in mercapturic acid formation. J Biol Chem 249: 7130

    Google Scholar 

  15. Hansson J, Berhane K, Castro VM, Jungnelius U, Mannervik B, Ringborg U (1991) Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid. Cancer Res 51: 94

    Google Scholar 

  16. Kessel D (1989) Resistance to antineoplastic drugs. CRC Press, Boca Raton, Florida

    Google Scholar 

  17. Kuzmich S, Tew KD (1991) Detoxification mechanisms and tumor cell resistance to anticancer drugs. Med Res Rev 11: 185

    Google Scholar 

  18. Leyland-Jones BR, Townsend AJ, Tu CPD, Cowan KH, Goldsmith ME (1991) Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human α class glutathioneS-transferase gene. Cancer Res 51: 587

    Google Scholar 

  19. Mannervik B (1985) The isoenzymes of glutathione transferase. Adv Enzymol 57: 357

    Google Scholar 

  20. Mannervik B, Alin P, Guthenberg C, Jensson H, Tahir MK, Warholm M, Jornvall H (1985) Identification of three classes of cytosolic glutathione transferse common to several mammalian species: correlation between structural data and enzymatic properties. Proc Natl Acad Sci USA 82: 7202

    Google Scholar 

  21. O'Dwyer PJ, LaCreta F, Nash S, Tinsley PW, Schilder R, Clapper ML, Tew KD, Panting L, Litwin S, Comis RL, Ozols RF (1991) Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res 51: 6059

    Google Scholar 

  22. Puchalski RB, Fahl WE (1990) Expression of recombinant glutathioneS-transferase π, Ya, or Yb1 confers resistance to alkylating agents. Proc Natl Acad Sci USA 87: 2443

    Google Scholar 

  23. Redwood WR, Colvin OM (1980) Transport of melphalan by sensitive and resistant L-1210 cells. Cancer Res 40: 1144

    Google Scholar 

  24. Robson CN, Lewis AD, Wolf CR, Hayes JD, Hall A, Proctor SJ, Harris AL, Hickson ID (1987) Reduced levels of drug-induced DNA cross-linking in nitrogen mustard resistant Chinese hamster ovary cells expressing elevated glutathioneS-transferase activity. Cancer Res 47: 6022

    Google Scholar 

  25. Sandberg M, Hansson K (1973) Determination of salicylazosulfapyridine in biological materials. Acta Pharm Suec 10: 107

    Google Scholar 

  26. Seidegard J, Vorachek WR, Pero RW, Pearson WR (1988) Hereditary differences in the expression of the human glutathione transferase active ontrans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA 85: 7293

    Google Scholar 

  27. Smith MT, Evans CG, Doane SP, Castro VM, Tahir MK, Mannervik B (1989) Denitrosation of 1,3-bis(2-chloroethyl)-1-nitrosourea by class μ glutathione transferases and its role in cellular resistance in rat brain tumor cells. Cancer Res 49: 2621

    Google Scholar 

  28. Teicher BA, Holden SA, Kelly MJ, Shea TC, Cucchi CA, Rosowsky A, Henner WD, Frei EF (1987) Characterization of a human squamous cell carcinoma cell line resistant tocis-diamminedichloroplatinum(II). Cancer Res 47: 388

    Google Scholar 

  29. Tew KD, Bomber AM, Hoffman SJ (1988) Ethacrynic acid and piriprost as enhancers of cytotoxicity in drug resistant and sensitive cell lines. Cancer Res 48: 3622

    Google Scholar 

  30. Tsuchida S, Sato K (1992) Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 27: 337

    Google Scholar 

  31. Van Doorn R, Leijdekkers CM, Henderson PT (1978) Synergistic effects of phorone on the hepatotoxicity of bromobenzene and paracetamol in mice. Toxicology 11: 225

    Google Scholar 

  32. Wang AL, Tew KD (1985) Increased glutathione-S-transferase activity in a cell line with acquired resistance to nitrogen mustard. Cancer Treat Rep 69: 677

    Google Scholar 

  33. Waxman DJ (1990) GlutathioneS-transferases: role in alkylating agent resistance and possible target for modulation chemotherapy—a review. Cancer Res 50: 6449

    Google Scholar 

  34. Xu BH, Singh SV (1992) Effect of buthionine sulfoximine and ethacrynic acid on cytotoxic activity of mitomycin C analogues BMY 25282 and BMY 25067. Cancer Res 52: 6666

    Google Scholar 

  35. Xu BH, Gupta V, Singh SV (1994) Mitomycin C sensitivity in human bladder cancer cells: possible role of glutathione and glutathione transferase in resistance. Arch Biochem Biophys 308: 164

    Google Scholar 

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Authors and Affiliations

  1. Cancer Research Laboratory, Mercy Cancer Institute, 1400 Locust Street, 15219, Pittsburgh, PA, USA

    Vicram Gupta, Jitesh P. Jani, Lynn Fields, Bing H. Xu, Mekala Sreevardhan & Shivendra V. Singh

  2. Department of Medicine, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Vicram Gupta, Samuel Jacobs & Mark Levitt

  3. Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, Texas, USA

    Sanjay Awasthi & Yogesh C. Awasthi

Authors
  1. Vicram Gupta
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  2. Jitesh P. Jani
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  3. Samuel Jacobs
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  4. Mark Levitt
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  5. Lynn Fields
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  6. Sanjay Awasthi
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  7. Bing H. Xu
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  8. Mekala Sreevardhan
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  9. Yogesh C. Awasthi
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  10. Shivendra V. Singh
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Additional information

This investigation was supported in part by a grant from the Pittsburgh Mercy Foundation and by USPHS grant CA 50638, awarded by the National Cancer institute

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Gupta, V., Jani, J.P., Jacobs, S. et al. Activity of melphalan in combination with the glutathione transferase inhibitor sulfasalazine. Cancer Chemother. Pharmacol. 36, 13–19 (1995). https://doi.org/10.1007/BF00685726

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  • DOI: https://doi.org/10.1007/BF00685726

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