Department of Molecular Therapeutics, The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
Best Pract Res Clin Haematol. 2009 Dec;22(4):577-82. doi: 10.1016/j.beha.2009.09.004.
The antifolates aminopterin and methotrexate have two firsts in the treatment of malignancy. Aminopterin was the first drug reported to cause remissions in children with acute lymphocytic leukaemia, and methotrexate (MTX), the antifolate that has supplemented aminopterin in the clinic, was the first drug that was shown to be curative for patients with a solid tumour, choriocarcinoma. More than 50 years after its introduction in the clinic, MTX is still being used and studied. The role of dihydrofolate reductase (DHFR), the principal target of aminopterin, has been studied extensively, and DHFR gene amplification and mutations have been implicated in drug resistance. Recent research focusses on studies of the translational regulation of DHFR and transfer of mutant DHFR and other drug resistance genes by viral vectors to protect haematopoietic cells. Based upon the detailed understanding of the mechanism of action of antifolates, both as inhibitors of DHFR and thymidylate syntase (TS), new agents have been developed that show effectiveness in the treatment of human malignancies. MTX remains a potent and widely used agent.
氨喋呤和甲氨蝶呤这两种抗叶酸药物在恶性肿瘤的治疗中有两个“第一”。氨喋呤是第一个被报道能使儿童急性淋巴细胞白血病缓解的药物，而甲氨蝶呤（MTX）作为临床上补充氨喋呤的抗叶酸药物，是第一个被证明能治愈实体瘤绒癌的药物。在临床应用 50 多年后，MTX 仍在被使用和研究。氨喋呤的主要靶标二氢叶酸还原酶（DHFR）的作用已被广泛研究，DHFR 基因扩增和突变与耐药性有关。最近的研究集中在 DHFR 的翻译调控以及通过病毒载体转移突变的 DHFR 和其他耐药基因以保护造血细胞上。基于对抗叶酸药物作为二氢叶酸还原酶和胸苷酸合成酶（TS）抑制剂的作用机制的详细了解，已经开发出了一些新的药物，这些药物在治疗人类恶性肿瘤方面显示出了有效性。MTX 仍然是一种强效且广泛使用的药物。
