The Division of Medicinal Chemistry, School of Pharmacy, The University of Connecticut, Storrs, Connecticut 06269, U.S.A.
Biosci Rep. 2024 Sep 25;44(9). doi: 10.1042/BSR20231382.
Purine and pyrimidine nucleotides are crucial building blocks for the survival of cells, and there are layers of pathways to make sure a stable supply of them including de novo nucleotide biosynthesis. Fast-growing cells including cancer cells have high demand for nucleotide, and they highly utilize the nucleotide biosynthesis pathways. Due to the nature of the fast-growing cells, they tend to make more errors in replication compared with the normal cells. Naturally, DNA repair and DNA lesion bypass are heavily employed in cancer cells to ensure fidelity and completion of the replication without stalling. There have been a lot of drugs targeting cancer that mimic the chemical structures of the nucleobase, nucleoside, and nucleotides, and the resistance toward those drugs is a serious problem. Herein, we have reviewed some of the representative nucleotide analog anticancer agents such as 5-fluorouracil, specifically their mechanism of action and resistance is discussed. Also, we have chosen several enzymes in nucleotide biosynthesis, DNA repair, and DNA lesion bypass, and we have discussed the known and potential roles of these enzymes in maintaining genomic fidelity and cancer chemotherapy.
嘌呤和嘧啶核苷酸是细胞生存的关键构建模块，有许多途径来确保它们的稳定供应，包括从头核苷酸生物合成。包括癌细胞在内的快速生长的细胞对核苷酸的需求很高，它们高度利用核苷酸生物合成途径。由于快速生长细胞的性质，与正常细胞相比，它们在复制过程中更容易出错。自然而然，DNA 修复和 DNA 损伤绕过在癌细胞中被大量利用，以确保复制的保真度和完成，而不会停滞不前。有很多针对癌症的药物模拟核苷酸碱基、核苷和核苷酸的化学结构，这些药物的耐药性是一个严重的问题。在此，我们综述了一些代表性的核苷酸类似物抗癌药物，如 5-氟尿嘧啶，特别讨论了它们的作用机制和耐药性。此外，我们选择了核苷酸生物合成、DNA 修复和 DNA 损伤绕过中的几种酶，并讨论了这些酶在维持基因组保真度和癌症化疗中的已知和潜在作用。
