Nagura E
Dept. of Medicine, National Chubu Hospital.
Gan To Kagaku Ryoho. 1988 Oct;15(10):2882-7.
Methotrexate (MTX), a folic acid antagonist, is among the most active known drugs for clinical cancer therapy. The mechanisms of resistance to MTX have been extensively studied, and several mechanisms have been reported so far. Those are decreased cell permeability, increased synthesis of dihydrofolate reductase (DHFR), which is the target enzyme of MTX, decreased polyglutamation of MTX, and decreased binding capacity of MTX to DHFR. Recent basic studies revealed that an increase of DHFR synthesis is the result of a proportional amplification of DHFR gene, and that polyglutamation of MTX plays an important role in its action. High-dose methotrexate (HDMTX) therapy has a good rationale for overcoming MTX resistance. However, many clinical trials of HDMTX during past decade have not demonstrated any apparent clinical efficacy except childhood ALL and ostosarcoma. Further research would be necessary for the improvement of the therapy using MTX.
甲氨蝶呤（MTX）是一种叶酸拮抗剂，是临床癌症治疗中已知最有效的药物之一。对MTX耐药的机制已得到广泛研究，目前已报道了几种机制。这些机制包括细胞通透性降低、MTX的靶酶二氢叶酸还原酶（DHFR）合成增加、MTX的多聚谷氨酸化减少以及MTX与DHFR的结合能力降低。最近的基础研究表明，DHFR合成增加是DHFR基因比例性扩增的结果，并且MTX的多聚谷氨酸化在其作用中起重要作用。大剂量甲氨蝶呤（HDMTX）疗法有充分的理由来克服MTX耐药性。然而，在过去十年中，许多HDMTX的临床试验除了在儿童急性淋巴细胞白血病和骨肉瘤中之外，并未显示出任何明显的临床疗效。为了改进使用MTX的治疗方法，还需要进一步的研究。
