急性早幼粒细胞白血病对全反式维甲酸耐药的机制及其逆转

目的　揭示急性早幼粒细胞白血病 (APL)产生维甲酸耐药的机制 ,探讨耐药性逆转的方法。方法　MTT法测定细胞增殖 ,极限稀释法诱导APL细胞耐药性。RT PCR及流式细胞仪测定MDR1、消炎痛及PGE1增殖影响实验分别间接测定GST酶活性或cAMP作用。干扰素、高三尖杉酯碱(HHT)及三氧化二砷 (As2 O3 )进行体外耐药细胞逆转实验。结果　对全反式维甲酸 (ATRA)耐药的HL6 0细胞MDR1阴性 ,初发时MDR1为阴性的APL患者复发后仍为阴性。消炎痛对耐药的HL6 0增殖分化无影响 ,前列腺素E(PGE)可部分恢复ATRA对耐药HL6 0的作用。干扰素可明显逆转HL6 0的耐药性。As2 O3 与HHT对ATRA耐药的HL6 0细胞有明显作用。结论　APL细胞耐药并非多药耐药 ,消炎痛或干扰素明显逆转其耐药性 ,ATRA与As2 O3 化疗药无交叉耐药性。

Drug resistance of acute promyelocytic leukemia (APL) to all-trans retinoic acid (ATRA) and its reversion

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.