Pastor-Anglada M, Felipe A, Casado F J
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Spain.
Trends Pharmacol Sci. 1998 Oct;19(10):424-30. doi: 10.1016/s0165-6147(98)01253-x.
Nucleoside analogues used in cancer and anti-viral therapies interfere with nucleotide metabolism and DNA replication, thus inducing their pharmacological effects. A long-awaited goal in the understanding of the pharmacological properties of these molecules, that is the molecular characterization of nucleoside plasma-membrane transporters, has been achieved very recently. These carrier proteins are encoded by at least two gene families and new isoforms remain to be identified. Direct demonstration of translocation of these drugs by nucleoside transporters has already been provided and most of them can inhibit natural nucleoside transport, probably in a competitive manner. The expression of these genes is clearly tissue-specific and might depend on the differentiated status of a cell. This is relevant because the sensitivity of a cell to a drug can depend on the type of nucleoside carrier expressed, and the drug itself might modulate nucleoside carrier expression. In this article, Marçal Pastor-Anglada, Antonio Felipe and Javier Casado discuss recent studies on the regulation of nucleoside carrier expression and of the molecular determinants of substrate specificity. Better knowledge of these will contribute to an improved design of therapies based on nucleoside derivatives.
用于癌症和抗病毒治疗的核苷类似物会干扰核苷酸代谢和DNA复制，从而产生其药理作用。了解这些分子药理特性的一个长期目标，即核苷质膜转运蛋白的分子特征，最近已经实现。这些载体蛋白由至少两个基因家族编码，新的亚型仍有待鉴定。核苷转运蛋白对这些药物转运的直接证据已经得到，并且它们中的大多数可能以竞争性方式抑制天然核苷转运。这些基因的表达具有明显的组织特异性，可能取决于细胞的分化状态。这很重要，因为细胞对药物的敏感性可能取决于所表达的核苷载体类型，而且药物本身可能会调节核苷载体的表达。在本文中，马尔卡尔·帕斯托-安格拉达、安东尼奥·费利佩和哈维尔·卡萨多讨论了关于核苷载体表达调控和底物特异性分子决定因素的最新研究。对这些方面的深入了解将有助于改进基于核苷衍生物的治疗方案设计。
