Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate.
Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate.
复制标题
小剂量口服甲氨蝶呤治疗类风湿性关节炎患者外周血淋巴细胞二氢叶酸还原酶升高。
DOI：
10.1002/art.1780300402
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发表时间：
1987
影响因子：
--
通讯作者：
Bertino,JR
中科院分区：
文献类型：
--
作者：
Rodenhuis,S;Kremer,JM;Bertino,JR
由于先前观察到长期甲氨蝶呤（MTX）治疗类风湿性关节炎（RA）后临床反应的平台期，我们研究了这种治疗是否可能导致对药物的获得性耐药。我们研究了11例接受MTX治疗中位时间为43个月的RA患者外周血单个核细胞中二氢叶酸还原酶（DHFR） （MTX的靶酶）的活性。与接受其他缓效药物治疗的6例RA患者细胞中的酶水平相比，酶水平明显升高。其中7例患者的DNA定量点印迹分析未发现DHFR基因扩增的证据。未观察到DHFR水平升高与治疗反应或每周甲氨喋呤剂量之间的相关性。6例DHFR水平升高患者的植物血凝素刺激的外周血淋巴细胞在体外未显示MTX耐药的证据。增加的DHFR水平可能是由于MTX与酶结合，这可能阻断正常的降解途径；它们似乎并不是即将出现耐药性的标志。
Because of a previously observed plateau of clinical response after long‐term methotrexate (MTX) therapy for rheumatoid arthritis (RA), we investigated whether such treatment might lead to acquired resistance to the drug. We studied the activity of dihydrofolate reductase (DHFR) (the target enzyme of MTX) in peripheral blood mononuclear cells of 11 RA patients who had been treated with MTX for a median of 43 months. The enzyme levels were markedly increased compared with levels found in the cells of 6 RA patients treated with other slow‐acting drugs. Quantitative dot‐blot analysis of DNA from 7 of these patients showed no evidence of DHFR gene amplification. No correlation was observed between increased levels of DHFR and either response to therapy or to the weekly MTX dosage. Phytohemagglutinin‐stimulated peripheral blood lymphocytes from 6 patients with increased levels of DHFR showed no evidence of MTX resistance in vitro. The increased DHFR levels may result from binding of MTX to the enzyme, which may block the normal degradation pathways; they do not appear to be a marker of impending drug resistance.