Evidence for the involvement of the glutathione pathway in drug resistance in AML.
We have studied altered drug detoxification through the glutathione pathway as a possible mechanism of resistance in 38 patients with AML. GST alpha, mu and pi 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 GST alpha 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 GST mu 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 GST mu expression appeared to co-express MRP (p < 0.05). In vitro drug modulation studies, comparing the cytotoxic effect of doxorubicin +/- ethacrynic acid at 6.5 microM 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.
Sargent
J M
JM
Pembury Hospital, Kent, United Kingdom.
Williamson
C
C
Hall
A G
AG
Elgie
A W
AW
Taylor
C G
CG
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity*; D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005978:Glutathione; D005982:Glutathione Transferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins