Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK.
Cells. 2022 Feb 20;11(4):739. doi: 10.3390/cells11040739.
Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.
从头合成和核苷补救。从头合成途径从氨基酸和葡萄糖合成核苷酸，而补救途径回收 DNA 或 RNA 降解过程中形成的核苷或碱基。与高度依赖从头合成的高增殖非恶性细胞不同，癌细胞可以切换到核苷补救途径以维持有效的 DNA 复制。嘧啶从头合成仍然是癌症治疗的目标，几种抑制剂在癌细胞和体内模型中显示出有希望的结果。然而，在 20 世纪 80 年代和 90 年代，几种现有的嘧啶合成抑制剂的临床试验中观察到反应不佳。为了克服临床试验中观察到的局限性，建议单独或与嘧啶从头抑制剂联合靶向嘧啶补救。尽管这种方法最初显示出有希望的结果，但最近才重新受到关注。在这里，我们讨论了单独或与嘧啶从头合成抑制剂联合靶向嘧啶补救途径以克服各种临床前癌症模型和临床试验中常用代谢物的局限性，用于 DNA 复制的重新发现。我们还强调了嘧啶合成以及嘧啶补救作为免疫疗法中一个有前途的靶点的新出现的靶标。
