In the past 65 years, antifolates targeting folate metabolism played a pivotal role in drug treatment of malignant, microbial, parasitic and chronic inflammatory diseases. Drug discovery of novel antifolates with improved properties and superior activities remains an attractive strategy both in academia and in the pharmaceutical industry. Among novel antifolates are pemetrexed which primarily targets thymidylate synthase as well as pralatrexate which blocks dihydrofolate reductase, and displays enhanced transport and cellular retention properties. The present review describes the evolution and pharmacological activity of antifolates and prospects for the development of the next generation antifolates. Pre-clinical and clinical studies identified a plethora of mechanisms of antifolate resistance that are a primary hindrance to curative cancer chemotherapy; these are frequently associated with qualitative and/or quantitative alterations in influx and/or efflux transporters of antifolates and in folate-dependent enzymes. Current advances including for example the deciphering of the dominant folate transporter proton-coupled folate transporter (PCFT/SLC46A1) facilitated the synthesis of experimental antifolates aimed at selectively targeting solid tumor cells, which reside in an acidic microenvironment where PCFT supposedly functions optimally. Moreover, drugs that are structurally and mechanistically distinct from folates were conjugated to folic acid (e.g. Vintafolide/EC145, a folic acid desacetylvinblastine conjugate) to facilitate endocytosis via the folate receptor (FR) which is markedly overexpressed in various solid tumors. In an alternative approach, novel antifolates selectively targeting the FR but not other folate transporters are being developed (e.g. BGC 945). Hence, targeting mechanisms of antifolate-resistance could facilitate the development of rationally-based novel antifolates and strategies that overcome chemoresistance.

中文翻译：

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癌症治疗中的抗叶酸药物：抗药性的结构，活性和机制。

在过去的65年中，靶向叶酸代谢的抗叶酸药物在恶性，微生物，寄生虫和慢性炎症性疾病的药物治疗中起着关键作用。在学术界和制药业中，发现具有改善的性能和优异活性的新型抗叶酸药物仍然是一个有吸引力的策略。在新的抗叶酸药物中，主要是针对胸苷酸合酶的培美曲塞以及阻断二氢叶酸还原酶并显示出增强的转运和细胞保留特性的普拉美酯。本综述描述了抗叶酸药物的进化和药理活性以及下一代抗叶酸药物的开发前景。临床前和临床研究确定了多种抗叶酸耐药性机制，这些机制是治愈性癌症化学疗法的主要障碍。这些经常与抗叶酸的流入和/或外排转运蛋白和叶酸依赖性酶的定性和/或定量改变有关。当前的进展包括例如对主要叶酸转运蛋白与质子偶联的叶酸转运蛋白（PCFT / SLC46A1）的解密，促进了旨在选择性靶向实体瘤细胞的实验性抗叶酸药物的合成，这些肿瘤细胞位于酸性微环境中，PCFT可能发挥最佳作用。此外，将在结构和机理上与叶酸不同的药物与叶酸结合（例如Vintafolide / EC145，叶酸去乙酰长春碱结合物）以促进通过叶酸受体（FR）的内吞作用，而叶酸受体在各种实体瘤中均明显过表达。在替代方法中，正在开发选择性靶向FR而不是其他叶酸转运蛋白的新型抗叶酸药物（例如BGC 945）。因此，抗叶酸药物的靶向机制可以促进基于理性的新型抗叶酸药物和克服化学耐药性的策略的开发。