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Raised intracellular glutathione levels correlate with in vitro resistance to cytotoxic drugs in leukaemic cells from patients with acute lymphoblastic leukaemia

Lookup NU author(s): Dr Linda Hogarth, Dr Michael Reid, Professor Stephen Proctor, Dr Peter Hamilton, Dr Andrew Hall


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Lymphoblasts were separated from the peripheral blood or bone marrow of 19 children (age 1-15, median 4 years) and 13 adults (age 18-59, median 47 years) with acute lymphoblastic leukaemia (ALL). Twenty-one samples were examined at presentation (16 from children and five from adults) and 13 at relapse (three children and ten adults). Glutathione (GSH) levels in leukaemic blasts were compared with in vitro sensitivity to a variety of cytotoxic drugs assessed using 3-(4-5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. There was a statistically significant positive correlation between GSH levels and in vitro sensitivity to daunorubicin (Spearman's rank correlation coefficient r(s) = 0.38, p < 0.04), melphalan (r(s) = 0.39, p < 0.04) and prednisolone (r(s) = 0.48, p < 0.01), but not mitozantrone, etoposide or 6-thio-guanine. There was no statistically significant difference in median GSH levels between blasts from children and adults or between samples taken at presentation or relapse. The sample median GSH levels in blasts from patients who responded to therapy (n = 21) and those who did not (n = 7) were 1.05 fmol/cell (97.3% confidence interval (CI) 0.78-1.52) and 2.66 fmol/cell (98.4% CI 0.53-5) respectively, and this difference was statistically significant (p < 0.02, Mann-Whitney U test). In two patients for whom paired samples were available, GSH levels in blasts on relapse were greater than 2-fold higher than on presentation. These results provide evidence that elevations of GSH in leukaemic blasts may be associated with resistance to drugs used in the treatment of children and adults with ALL.

Publication metadata

Author(s): Maung, Z. T., Hogarth, L. A., Reid, M. M., Proctor, S. J., Hamilton, P. J., Hall, A. G.

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 1994

Volume: 8

Issue: 9

Pages: 1487-1491

Print publication date: 01/09/1994

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

PubMed id: 8090028