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Cancer Chemotherapy and Pharmacology

, Volume 33, Issue 3, pp 210–214 | Cite as

Differential cytotoxicity of buthionine sulfoximine to “normal” and transformed human lung fibroblast cells

  • X. Steven Wan
  • Daret K. St. Clair
Original Articles Glutathione Modulation, Buthionine Sulfoximine, Cytotoxicity

Abstract

Glutathione (GSH) depletion has been studied extensively as a possible means to sensitize tumor cells to radiation treatment and chemotherapy. The present study was undertaken to compare the cytotoxicity of GSH depletion in normal and transformed cells. The results showed that specific inhibition of GSH synthesis byl-buthionine sulfoximine (BSO) caused significantly higher cytotoxicity in “normal” human-lung fibroblast cells than in their transformed counterparts. This finding suggests a possibility that depletion of GSH could be more harmful to normal cells than to transformed and/or tumor cells and that the selective cytotoxicity of BSO to normal cells could limit its potential as an effective sensitizer for cancer treatment.

Keywords

Tumor Cell Glutathione Normal Cell Human Lung Specific Inhibition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Allen RG, Farmer KJ, Sohal RS (1984) Effect of diamide administration on longevity, oxygen consumption, superoxide dismutase, catalase, inorganic peroxides and glutathione in the adult housefly,Musca domestica. Comp Biochem Physiol 78: 31–33Google Scholar
  2. 2.
    Argiles JM, Lopez-Soriano FJ (1990) Why do cancer cells have such a high glycolytic rate? Med Hypothesis 32: 151–155Google Scholar
  3. 3.
    Arrick BA, Nathan CF (1984) Glutathione metabolism as a determinant of therapeutic efficacy: a review. Cancer Res 44: 4224–4232Google Scholar
  4. 4.
    Biaglow JE, Varnes ME, Clark EP, Epp ER (1983) The role of thiols in cellular response to radiation and drugs. Radiat Res 95: 437–455Google Scholar
  5. 5.
    Biaglow JE, Varnes ME, Epp ER, Clark EP, Astor MA (1984) Factors involved in depletion of glutathione from A549 human lung carcinoma cells: implications for radiotherapy. Int J Radiat Oncol Biol Phys 10: 1221–1227Google Scholar
  6. 6.
    Biaglow JE, Varnes ME, Epp ER, Clark EP, Tuttle SW, Held KD (1989) Role of glutathione in the aerobic radiation response. Int J Radiat Oncol Biol Phys 16: 1311–1314Google Scholar
  7. 7.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254Google Scholar
  8. 8.
    Bump EA, Taylor YC, Brown JM (1983) Role of glutathione in the hypoxic cell cytotoxicity of misonidazole. Cancer Res 43: 997–1002Google Scholar
  9. 9.
    DeGraff WG, Russo A, Mitchell JB (1985) Glutathione depletion greatly reduces neocarzinostatin cytotoxicity in Chinese hamster V79 cells. J Biol Chem 260: 8312–8315Google Scholar
  10. 10.
    Dusre L, Mimnaugh EG, Myers CE, Sinha BK (1989) Potentiation of doxorubicin cytotoxicity by buthionine sulfoximine in multidrug-resistant human breast tumor cells. Cancer Res 49: 511–515Google Scholar
  11. 11.
    Green JA, Vistica DT, Young RC, Hamilton TC, Rogan AM, Ozols RF (1984) Potentiation of melphalan cytotoxicity in human ovarian cancer cell lines by glutathione depletion. Cancer Res 44: 5427–5431Google Scholar
  12. 12.
    Gregory JD (1955) The stability ofN-ethylmaleimide and its reaction with sulfhydryl groups. J Am Chem Soc 77: 3922–3923Google Scholar
  13. 13.
    Griffith OW, Meiste A (1979) Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem 254: 7558–7560Google Scholar
  14. 14.
    Harris JW (1979) Mammalian cell studies with diamide. Pharmacol Ther 7: 375–391Google Scholar
  15. 15.
    Kosower EM, Correa W, Kinon BJ, Kosower NS (1972) Glutathione. VII. Differentiation among substrates by the thiol-oxidizing agent, diamide. Biochim Biophys Acta 264: 39–44Google Scholar
  16. 16.
    Kramer RA, Greene K, Ahmad S, Vistica DT (1987) Chemosensitization ofl-phenylalanine mustard by the thiol-modulating agent buthionine sulfoximine. Cancer Res 47: 1593–1597Google Scholar
  17. 17.
    Martensson J, Jain A, Stole E, Frayer W, Auld PAM, Meister A (1991) Inhibition of glutathione synthesis in the newborn rat: a model for endogenously produced oxidative stress. Proc Natl Acad Sci USA 88: 9360–9364Google Scholar
  18. 18.
    Meister A, Anderson ME (1983) Glutathione. Annu Rev Biochem 52: 711–760Google Scholar
  19. 19.
    Meredith MJ, Reed DJ (1983) Depletion in vitro of mitochondrial glutathione in rat hepatocytes and enhancement of lipid peroxidation by Adriamycin and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Biochem Pharmacol 32: 1383–1388Google Scholar
  20. 20.
    Mitchell JB, Cook JA, DeGraff W, Glatstein E, Russo A (1989) Glutathione modulation in cancer treatment: will it work? Int J Radiat Oncol Biol Phys 16: 1289–1295Google Scholar
  21. 21.
    Mitchell JB, Russo A (1986) The role of glutathione in radiation and drug induced cytotoxicity. Br J Cancer [Suppl] 55: 96–104Google Scholar
  22. 22.
    Martensson J, Meister A (1991) Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. Proc Natl Acad Sci USA 88: 4656–4660Google Scholar
  23. 23.
    O'Dwyer PJ, Hamilton TC, Young RC, LaCreta FP, Carp N, Tew KD, Padavic K, Comis RL, Ozols RF (1992) Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results. J Natl Cancer Inst 48: 264–267Google Scholar
  24. 24.
    Ozols RF, Louie KG, Plowman J, Behrens BC, Fine RL, Dykes D, Hamilton TC (1987) Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor-bearing nude mice by buthionine sulfoximine depletion of glutathione. Biochem Pharmacol 36: 147–153Google Scholar
  25. 25.
    Phillips TL, Mitchell JB, DeGraff W, Russo A, Glatstein E (1986) Variation in sensitizing efficiency for SR 2508 in human cells dependent on glutathione content. Int J Radiat Oncol Biol Phys 12: 1627–1635Google Scholar
  26. 26.
    Russo A, DeGraff W, Friedman F, Mitchell JB (1986) Selective modulation of glutathione levels in human normal versus tumor cells and subsequent differential response to chemotherapy drugs. Cancer Res 46: 2845–2848Google Scholar
  27. 27.
    Schecter RL, Woo A, Duong M, Batist G (1991) In vivo and in vitro mechanisms of drug resistance in a rat mammary carcinoma model. Cancer Res 51: 1434–1442Google Scholar
  28. 28.
    Skov KA, MacPhail HS (1992) Effect of BSO on the radiation response at low (0–4 Gy) doses. Int J Radiat Oncol Biol Phys 22: 533–536Google Scholar
  29. 29.
    Tedeschi M, Bohm S, Re FD, Oriana S, Spatti GB, Tognella S, Zunino F (1990) Glutathione and detoxification. Cancer Treat Rev 17: 203–208Google Scholar
  30. 30.
    Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: application to mammalian blood and other tissues. Anal Biochem 27: 502–522Google Scholar
  31. 31.
    Wan XS, St Clair DK (1993) Thiol-modulating agents increase manganese superoxide dismutase activity in human lung fibroblasts. Arch Biochem Biophys 304: 89–93Google Scholar
  32. 32.
    Warburg O (1956) On the origin of cancer cells. Science 123: 309–314Google Scholar
  33. 33.
    Wong GHW, Elwell JH, Oberley LW, Goeddel DV (1989) Manganese superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell 58: 923–931Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • X. Steven Wan
    • 1
  • Daret K. St. Clair
    • 1
  1. 1.Graduate Center for ToxicologyUniversity of KentuckyLexingtonUSA

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