二氢叶酸还原酶抑制剂在肿瘤治疗中的研究进展-中国现代应用药学.pdf

二氢叶酸还原酶抑制剂在肿瘤治疗中的研究进展 李丹1 2 2,3* ，杨丽君 ，翁勤洁 (1. 国家食品药品监督管理总局药品审评中心，北京 100038 ；2.浙江大学药学院，杭州 310058 ；3.浙江 大学药物安全评价研究中心，杭州 310058)  摘要：二氢叶酸还原酶(dihydrofolate reductase ，DHFR)是合成DNA 的必需前体物胸腺嘧啶脱氧核苷(dTMP)的关键酶，在 细胞增殖中起重要作用，是肿瘤治疗的重要靶点。抑制DHFR 能够抑制dTMP 的生物合成，进而抑制肿瘤细胞的生长或 增殖，在临床上显示抗肿瘤的作用。近年来，该类药物的神经毒性极大限制了其临床广泛应用。基于此，本文对 DHFR 抑制剂药物在肿瘤治疗中的应用进行综述，并介绍药物相应的神经毒副作用(药物剂量限制性不良反应) ，探讨 DHFR 抑 制剂药物在肿瘤治疗中的发展现状及为临床合理用药减少神经毒性反应提供指导。 关键词：二氢叶酸还原酶(DHFR)；抑制剂；抗肿瘤；神经毒性 中图分类号：R966 文献标志码：A 文章编号：1007-7693(2017)10-1496-05 DOI: 10.13748/j.cnki.issn1007-7693.2017.10.031 引用本文：李丹, 杨丽君, 翁勤洁. 二氢叶酸还原酶抑制剂在肿瘤治疗中的研究进展[J]. 中国现代应用药学, 2017, 34(10): 1496-1500. Progress and Study of Dihydrofolate Reductase Inhibitors in Tumor Therapy 1 2 2,3* LI Dan , YANG Lijun , WENG Qinjie (1.Center for Drug Evaluation of China Food and Drug Administration, Beijing 100038, China; 2.College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058 , China; 3.Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058 , China) ABSTRACT: Dihydrofolate reductase(DHFR) is a key enzyme for the synthesis of DNA precursor deoxythymidine(dTMP), which plays an important role in cell proliferation, and is an important target for tumor therapy. Inhibition of DHFR can inhibit dTMP biosynthesis, thereby inhibiting the growth or the appreciation of tumor cells, which shows anti-tumor effect in clinic. In recent years, the neurotoxicity of these drugs has greatly limited its clinical application. Based on this, this paper reviewed the application of DHFR inhibitors in tumor therapy, and introduced the corresponding neurotoxic side effects (drug dose restrictive adverse reaction), to explore the developmentof DHFR inhibitors in tumor therapy and to provide guidance for clinical rational drug use to reduce neurotoxicity. KEY