Galmarini Carlos M, Jordheim Lars, Dumontet Charles
Inserm 590-Laboratoire de Cytologie Analytique, Faculté de Médecine Rockefeller, Lyon, France.
Expert Rev Anticancer Ther. 2003 Oct;3(5):717-28. doi: 10.1586/14737140.3.5.717.
Pyrimidine nucleoside analogs are essential components of hematological malignancy therapy and are also used in the treatment of solid tumors. These agents act as antimetabolites, compete with physiologic pyrimidine nucleosides and, consequently, interact with a large number of intracellular targets to induce cytotoxicity. Pyrimidine nucleoside analogs share some common characteristics, such as requiring both transport by specific membrane transporters and intracellular metabolism. However, these compounds differ in regards to their preferential interaction with certain targets, which may explain why some compounds are more effective against rapidly proliferating tumors and others against neoplasias with a more protracted evolution. Recent progress in the identification and characterization of nucleoside transporters and the enzymes of nucleoside metabolism, as well as an understanding of the molecular mechanisms of anticancer nucleoside activity, provides opportunities for the development of new pyrimidine nucleoside analogs. Strategies to optimize intracellular analog accumulation and to enhance cancer cell selectivity are proving beneficial in clinical trials.
嘧啶核苷类似物是血液系统恶性肿瘤治疗的重要组成部分，也用于实体瘤的治疗。这些药物作为抗代谢物，与生理性嘧啶核苷竞争，因此与大量细胞内靶点相互作用以诱导细胞毒性。嘧啶核苷类似物具有一些共同特征，例如需要通过特定的膜转运蛋白进行转运并在细胞内进行代谢。然而，这些化合物在与某些靶点的优先相互作用方面存在差异，这可能解释了为什么一些化合物对快速增殖的肿瘤更有效，而另一些对进化更缓慢的肿瘤更有效。核苷转运蛋白和核苷代谢酶的鉴定与表征方面的最新进展，以及对抗癌核苷活性分子机制的理解，为开发新的嘧啶核苷类似物提供了机会。在临床试验中，优化细胞内类似物积累和提高癌细胞选择性的策略已证明是有益的。
