DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.

通过介导癌症相关基因的表观遗传沉默，DNA甲基化在癌症病因中起着关键作用。由于已经了解了异常的DNA甲基化与癌症之间的关系，因此在开发通过抑制DNA甲基化而起作用的抗癌疗法方面的研究激增。从1980年代第一种DNA低甲基化药物的发现到最近发现的第二代前药，已经发表了过多的研究，这些研究描述了这些药物在临床前各个阶段基于DNA低甲基化的抗肿瘤作用。调查和临床开发的后期阶段。这篇综述是对过去40年来发表的文献的全面报道，涉及按时间顺序排列的迄今为止发现的核苷DNA甲基化抑制剂。该综述将为读者提供有关这些药物的作用机理，去甲基化和重新表达各种癌症相关基因的功效，抗肿瘤活性，细胞毒性概况，稳定性和生物利用度的完整见解。综述进一步提出了对氮杂核苷药物的初级和次级抗性的众所周知的机制。最后，该综述突出了DNA低甲基化表位药物作为化学增敏剂和/或引发剂的普遍作用，并概括了这些药物与其他表观遗传学剂，常规化学药物或免疫疗法的组合性癌症预防作用。这份全面的综述分析了核苷DNA甲基化抑制剂的有益特性和缺点，