Cancer research: from folate antagonism to molecular targets
Cancer research: from folate antagonism to molecular targets
复制标题
DOI：
10.1016/j.beha.2009.09.004
复制
发表时间：
2009-12-01
影响因子：
2.1
通讯作者：
Bertino, Joseph R.
中科院分区：
文献类型：
--
作者：
Bertino, Joseph R.
抗叶酸剂氨蝶呤和甲氨蝶呤在治疗恶性肿瘤方面有两个第一。氨蝶呤是第一种被报道能缓解儿童急性淋巴细胞白血病的药物，而氨甲喋呤（MTX）是第一种被证明能治愈实体瘤（绒毛膜癌）患者的药物，MTX是临床上补充氨蝶呤的抗叶酸剂。在其引入临床50多年后，MTX仍在使用和研究。二氢叶酸还原酶（DHFR）的作用，氨基蝶呤的主要目标，已被广泛研究，和DHFR基因扩增和突变有牵连的耐药性。近年来的研究主要集中在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。基于对叶酸拮抗剂的作用机制的详细理解，作为DHFR和胸苷酸合成酶（TS）的抑制剂，已经开发出在治疗人类恶性肿瘤中显示有效性的新药剂。MTX仍然是一种有效且广泛使用的药物。(c)2009年由Elsevier Ltd.出版
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. (c) 2009 Published by Elsevier Ltd.