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[Mechanisms of resistance to melphalan in leukemia cell line and reversal by interferon alpha]
Objectives:
To study the mechanisms of resistance to alkylating agent melphalan (Mel) in leukemia cell and to investigate effect of modulation of resistance to Mel by IFN alpha.
Methods:
A Mel-resistant variant of the leukemic cell line (K562/Mel) was developed in vitro by continuous exposure to Mel. The level of expression of several resistance-related gene in K562/Mel and the effect of reversal of resistance to Mel by IFN alpha were observed.
Results:
K562/Mel was 8.0-fold resistant to Mel and also cross-resistant to nitrogen mustand and thiophosphoramide, but not to carmustine and doxorubicin. This enhanced Mel resistance was associated with increased level of GST alpha gene and total GST, but not with increased level of expression of GST pi, GST mu, MDR-1 and Top-II gene. IFN alpha, at 500 IU/ml, a noncytotoxic dosage significantly increased the cytotoxicity of Mel to K562/Mel. The reversal of Mel resistance is related to the decrease of the level of expression of GST alpha gene.
Conclusion:
Resistance to Mel is associated with increased level of GST alpha gene and total GST in leukemic cell. IFN alpha can reverse Mel resistance.