antifolate耐药性的分子基础。
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Assaraf YG
antifolate耐药性的分子基础。
癌症转移启2007年3月,26 (1):153 - 81。
- PubMed ID
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17333344 (在PubMed]
- 文摘
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叶酸对扮演一个关键的角色在一个碳代谢很重要的生物合成嘌呤,thymidylate因此DNA复制。antifolate甲氨蝶呤被合理设计近60年前强有力地阻止folate-dependent酶二氢叶酸还原酶(DHFR)从而实现临时缓解儿童急性白血病。最近,这部小说抗raltitrexed及培美曲塞这一目标thymidylate合成酶(TS)和glycineamide核苷酸transformylase (GARTF)介绍了治疗结直肠癌和恶性胸膜间皮瘤。(反)叶酸是二价离子,主要使用减少叶酸载体(RFC)的细胞吸收。(反)叶酸保留细胞通过polyglutamylation folylpoly-gamma-glutamate合成酶催化的(台塑)。随着抗细胞内浓度的至关重要的药理活性,polyglutamylation antifolate细胞毒性的关键决定因素。然而,抗癌药物耐药性现象构成对治疗癌症化疗的主要障碍。临床前和临床研究发现了大量antifolate-resistance机制;这些是经常与定性和/或定量改变流入或流出的转运蛋白(反)叶酸以及folate-dependent酶。这些包括灭活突变和/或下调RFC和各种变化的目标酶DHFR, TS和台塑。 Furthermore, it has been recently shown that members of the ATP-binding cassette (ABC) superfamily including multidrug resistance proteins (MRP/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are low affinity, high capacity ATP-driven (anti)folate efflux transporters. This transport activity is in addition to their established facility to extrude multiple cytotoxic agents. Hence, by actively extruding antifolates, overexpressed MRPs and/or BCRP confer antifolate resistance. Moreover, down-regulation of MRPs and/or BCRP results in decreased folate efflux thereby leading to expansion of the intracellular folate pool and antifolate resistance. This chapter reviews and discusses the panoply of molecular modalities of antifolate-resistance in pre-clinical tumor cell systems in vitro and in vivo as well as in cancer patients. Currently emerging novel strategies for the overcoming of antifolate-resistance are presented. Finally, experimental evidence is provided that the identification and characterization of the molecular mechanisms of antifolate-resistance may prove instrumental in the future development of rationally-based novel antifolates and strategies that could conceivably overcome drug-resistance phenomena.