Matherly Larry H, Hou Zhanjun, Deng Yijun
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, The Cancer Biology Graduate Program, Detroit, MI 48201, USA.
Cancer Metastasis Rev. 2007 Mar;26(1):111-28. doi: 10.1007/s10555-007-9046-2.
This review attempts to provide a comprehensive overview of the biology of the physiologically and pharmacologically important transport system termed the "reduced folate carrier" (RFC). The ubiquitously expressed RFC has unequivocally established itself as the major transport system in mammalian cells and tissues for a group of compounds including folate cofactors and classical antifolate therapeutics. Loss of RFC expression or function may have potentially profound pathophysiologic consequences including cancer. For chemotherapeutic antifolates used for cancer such as methotrexate or pemetrexed, synthesis of mutant RFCs or loss of RFC transcripts and proteins results in antifolate resistance due to incomplete inhibition of cellular enzyme targets and insufficient substrate for polyglutamate synthesis. Since RFC was first cloned in 1994, tremendous advances have been made in understanding the complex transcriptional and posttranscriptional regulation of RFC, in identifying structurally and functionally important domains and amino acids in the RFC molecule as a prelude to establishing the mechanism of transport, and in characterizing the molecular defects in RFC associated with loss of transport in antifolate resistant cell line models. Many of the insights gained from laboratory models of RFC portend opportunities for modulating carrier expression in drug resistant tumors, and for designing a new generation of agents with improved transport by RFC or substantially enhanced transport by other folate transporters over RFC. Many of the advances in the basic biology of RFC in cell line models are now being directly applied to human cancers in the clinical setting, most notably pediatric acute lymphoblastic leukemia and osteogenic sarcoma.
本综述旨在全面概述一种在生理和药理方面都很重要的转运系统——“还原型叶酸载体”（RFC）的生物学特性。普遍表达的RFC已明确成为哺乳动物细胞和组织中一组化合物（包括叶酸辅因子和经典抗叶酸治疗药物）的主要转运系统。RFC表达或功能的丧失可能会产生潜在的深远病理生理后果，包括癌症。对于用于癌症治疗的化疗抗叶酸药物，如甲氨蝶呤或培美曲塞，突变型RFC的合成或RFC转录本和蛋白质的缺失会导致抗叶酸耐药性，这是由于细胞酶靶点未被完全抑制以及聚谷氨酸合成的底物不足所致。自1994年RFC首次被克隆以来，在理解RFC复杂的转录和转录后调控、确定RFC分子中结构和功能重要的结构域及氨基酸（作为建立转运机制的前奏）以及表征与抗叶酸耐药细胞系模型中转运丧失相关的RFC分子缺陷等方面都取得了巨大进展。从RFC的实验室模型中获得的许多见解预示着在耐药肿瘤中调节载体表达以及设计新一代药物的机会，这些药物通过RFC具有改善的转运能力，或者通过其他叶酸转运体比RFC具有显著增强的转运能力。RFC在细胞系模型中的基础生物学研究取得的许多进展现在正直接应用于临床环境中的人类癌症，最显著的是儿童急性淋巴细胞白血病和成骨肉瘤。
