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5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy

Abstract

5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2′-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.

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Acknowledgements

I am indebted to my colleagues, Drs AS Brank, X Cheng, R Eritja, VE Marquez and J Sufrin. The research on ODNs discussed here could not have been done without their help. I also thank M Boland and D Van Bemmel for their expert help with the figures. Supported in part by grants R21 CA091315-01 from the National Cancer Institute and DAMD 17-98-1-8215 from the Department of the Army Breast Cancer Program. Additional support came from the Cancer and Smoking Disease Research Program, Nebraska Department of Health, 97-15 and UNMC/Eppley Cancer Center.

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Christman, J. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21, 5483–5495 (2002). https://doi.org/10.1038/sj.onc.1205699

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