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Evidence for the involvement of the glutathione pathway in drug resistance in AML

Lookup NU author(s): Dr Andrew Hall


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We have studied altered drug detoxification through the glutathione pathway as a possible mechanism of resistance in 38 patients with AML. GST α, μ and π expressions were determined using immunocytochemistry, the median percentages of positive cells being 73% (range 0-98), 55% (range 0-99) and 97% (range 80-100) respectively. MRP expression was measured using MRPm6 MoAb and flow cytometry. Results were expressed as the ratio of fluorescence associated with MRP over that of an isotype matched control (median, 1.32 ; range 0.95-2.15). Statistical analyses showed a significant increase in GSTα expression in blast cells showing in vitro resistance to doxorubicin, with a median value of 78% positive cells compared to 41% in the sensitive group (p<0.02). There was a significant reduction, however, in GSTμ expression from a median value of 60% in newly presenting patients to 40% in a group of patients who had received previous cytotoxic therapy (p<0.02). Interestingly, patients with high GSTμ expression appeared to co-express MRP (p<0.05). In vitro drug modulation studies, comparing the cytotoxic effect of doxorubicin ±ethacrynic acid at 6.5μM resulted in only one significant increase in sensitivity (2.6-fold), out of 22 comparisons. These results support the theory that altered detoxification through the glutathione pathway contributes towards drug resistance in AML. Further studies using fresh blast cells are required to elucidate the importance of this mechanism for individual patients.

Publication metadata

Author(s): Sargent J, Williamson C, Hall A, Elgie A, Taylor C

Publication type: Article

Publication status: Published

Journal: Advances in Experimental Medicine and Biology

Year: 1999

Volume: 457

Pages: 205-209

Print publication date: 01/01/1999

ISSN (print): 0065-2598

ISSN (electronic):

PubMed id: 10500795