Glutathione in Childhood Acute Leukaemias

  • P. Kearns
  • R. Pieters
  • M. M. A. Rottier
  • A. J. P. Veerman
  • K. Schmiegalow
  • A. D. J. Pearson
  • A. G. Hall
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 457)


In order to test the hypothesis that glutathione (GSH) is an important determinant of treatment response in childhood acute leukaemia, blast cell GSH levels were studied in a cohort of children with acute lymphoblastic (ALL) and acute myeloid (AML) leukaemia.

In both ALL and AML, several indicators of poor prognosis are well established but the underlying molecular mechanisms leading to resistant disease are still poorly understood. GSH is an intracellular thiol implicated in the development of cytotoxic drug resistance and appears to be involved in the control of cell proliferation and apoptosis.

In this study, total GSH was measured in cryopreserved blasts from 62 childhood ALL and 13 AML patients. In ALL, high GSH levels were associated with a relatively poor prognosis. A positive correlation was demonstrated between the GSH level and presenting white cell count (WCC). GSH levels were significantly higher in T lineage ALL compared with B lineage and in AML blasts compared with ALL.

These results are supportive of GSH as prognostic indicator in childhood leukaemia and may suggest one mechanism of treatment failure. They imply that it may be possible to improve chemosensitivity by the use of known modulators of GSH synthesis.


Glutathione childhood leukaemia prognostic indicators drug resistance 


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  1. 1.
    Cotes J.E., Kantarjian H.M. Acute lymphoblastic leukemia. A comprehensive review with emphasis on biology and therapy. Cancer, 1995, 76, 2393–2417.CrossRefGoogle Scholar
  2. 2.
    Pieters R., Huismans D.R., Loonen A. H., Hahien K., Van Der Does-Van Den Berg A., Van Wering E.R. and Veerman A. J. P. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet, 1991, 338, 399–403.PubMedCrossRefGoogle Scholar
  3. 3.
    O’Brien M.L. and Tew K.D. Glutathione and related enzymes in multidrug resistance. Eur. J. Cancer, 1996, 967–978.Google Scholar
  4. 4.
    Frischer H., Kennedy E J., Chigurupati R. and Sivarajan M. Glutathione, cell proliferation, and l,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia. Journal of Clinical Investigation, 1993, 92, 2761–2767.PubMedCrossRefGoogle Scholar
  5. 5.
    Watson R. W. G., Rotstein O. D., Nathens A.B., Dackiw A.P.B. and Marshall J. C. Thiol-mediated redox regulation of neutrophil apoptosis. Surgery, 1996, 120, 150–158.PubMedCrossRefGoogle Scholar
  6. 6.
    Ozols R.F., O’Dwyer P.J., Hamilton T.C. and Young R. C. The role of glutathione in drug resistance. Cancer Treat. Rev., 1990, 17, 45–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Ferraris A. M., Rolfo M., Mangerini R. and Gaetani G. F. Increased glutathione in chronic lymphocytic leukemia lymphocytes, Am. J. Hematol., 1994, 47, 237–238.PubMedCrossRefGoogle Scholar
  8. 8.
    Maung Z. T., Reid M. M., Matheson E., Taylor P. R. A., Proctor S. J. and Hall A. G. Corticosteroid resistance is increased in lymphoblasts from adults compared with children: Preliminary results of in vitro drug sensitivity study in adults with acute lymphoblastic leukaemia. Br. J. Haematol., 1995, 91, 93–100.PubMedCrossRefGoogle Scholar
  9. 9.
    Paydas S., Yuregir G. T., Sahin B., Seyrek E. and Burgut R. Intracellular glutathione content in leukemias. Oncology, 1995, 52, 112–115.PubMedCrossRefGoogle Scholar
  10. 10.
    Kearns P. R. and Hall A. G. Microtitre plate technique for the measurement of glutathione in fresh and cryopreserved lymphoblasts using the enzyme recycling method. Methods in Molecular Medicine, 1999, (in press).Google Scholar
  11. 11.
    Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248–254.PubMedCrossRefGoogle Scholar
  12. 12.
    Terradez P., Asensi M., Lasso della Vega M. C., Puertes I. R., Vina J. and Estrela J. M. Depletion of tumour glutathione in vivo by buthionine sulphoximine: Modulation by the rate of cellular proliferation and inhibition of cancer growth. Biochem. J., 1993, 292, 477–483.PubMedGoogle Scholar
  13. 13.
    Poot M., Teubert H., Rabinovitch P. S. and Kavanagh T. J. De novo synthesis of glutathione is required for both entry into and progression through the cell cycle. J. Cell. Physiol., 1995, 163, 555–560.PubMedCrossRefGoogle Scholar
  14. 14.
    Frischer H., Kennedy E. J., Chigurupati R. and Sivarajan M. Glutathione, cell proliferation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia. J. Clin. Invest., 1993, 92, 2761–2767.PubMedCrossRefGoogle Scholar
  15. 15.
    Kavanagh T. J., Grossmann A., Jaecks E. P., Jinneman J. C., Eaton D. L., Martin G. M. and Rabinovitch P. S. Proliferative capacity of human peripheral blood lymphocytes sorted on the basis of glutathione content. J. Cell. Physiol., 1990, 145, 472–480.PubMedCrossRefGoogle Scholar
  16. 16.
    Ngo E. O. and Nutter L. M. Status of glutathione and glutathione-metabolizing enzymes in menadione-resistant human cancer cells. Biochem. Pharmacol., 1994, 47, 421–424.PubMedCrossRefGoogle Scholar
  17. 17.
    Scarffe J. H., Hann I. M., Evans D. I. K., Morris-Jones P., Palmer M. K., Lilleyman J. S. and Crowther D. Relationship between the pretreatment proliferative activity of marrow blast cells and prognosis of acute lymphoblastic leukaemia of childhood. Br. J. Cancer, 1980, 41, 764–771.PubMedCrossRefGoogle Scholar
  18. 18.
    Siemann D. W. and Beyers K. L. In vivo therapeutic potential of combination thiol depletion and alkylating chemotherapy. British Journal of Cancer, 1993, 68, 1071–1079.PubMedCrossRefGoogle Scholar
  19. 19.
    Medh R. D., Gupta V. and Awasthi Y. C. Reversal of melphalan resistance in vivo and in vitro by modulation of glutathione metabolism. Biochem Pharmacol., 1991, 42, 439–441.PubMedCrossRefGoogle Scholar
  20. 20.
    Ozols R. F., Louie K. G., Plowman J., Behrens B. C., Fine R. L., Dykes D. and Hamilton T. C. Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor-bearing nude mice by buthionine sulfoximine depletion of glutathione. Biochem Pharmacol., 1987, 36, 147–153.PubMedCrossRefGoogle Scholar
  21. 21.
    O’Dwyer P. J., Hamilton T. C., Young R. C., LaCreta F. P., Carp N., Tew K. D., Padavic K., Comis R. L. and Ozols R. F. Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results. J. Natl. Cancer Inst., 1992, 84, 264–267.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • P. Kearns
    • 1
    • 2
  • R. Pieters
    • 1
  • M. M. A. Rottier
    • 1
  • A. J. P. Veerman
    • 1
  • K. Schmiegalow
    • 3
  • A. D. J. Pearson
    • 2
  • A. G. Hall
    • 2
  1. 1.Department of Paediatric Haematology and OncologyFree University HospitalAmsterdamThe Netherlands
  2. 2.Department of Paediatric Oncology Medical SchoolUniversity of Newcastle upon TyneUK
  3. 3.Department of Haematology and OncologyThe Juliane Marie CentreCopenhagenDenmark

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