Objective: To study the mechanism of drug resistance of APL to ATRA and the methods of reversion.
Methods: ATRA-resistant HL60 cell line and bone marrow (BM) leukemia cells from recurrent APL patients who did not respond to ATRA treatment were used in this study. Multiple drug resistance gene (mdr1) expression was determined by RT-PCR and flow cytometry. Cell proliferation and differentiation were assessed by MTT uptake and NBT reduction respectively.
Results: The response of ATRA-resistant HL60 and APL cells from recurrent patients to the differentiation inducing activity of ATRA was significantly reduced, and ATRA had little effect on cell proliferation. Expression of mdr-1 was nagative in ATRA-resistant HL60 cells. It was negative in resistant APL cells even after ATRA treatment. Arsenic trioxide and homoharringtonine (HHT) could inhibit proliferation of HL60 and ATRA-resistant HL60 cells, indicating no cross-resistance with ATRA. Interferon alpha (IFN-alpha) and PGE1 could significantly inhibit proliferation of ATRA-resistant HL60 cells and restore cell differentiation induced by ATRA.
Conclusion: Drug resistance of APL to ATRA is not related to mdr-1. It can be reversed by IFN-alpha. There is no cross-resistance between HHT or arsenic trioxide and ATRA.