title: DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer.
abstract: The DNA methyltransferase (DNMT) inhibitors azacytidine and decitabine are the most successful epigenetic drugs to date and are still the most widely used as epigenetic modulators, even though their application for oncological diseases is restricted by their relative toxicity and poor chemical stability. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one), a more stable and less toxic cytidine analog, is another inhibitor of DNMT with concomitant inhibitory activity towards cytidine deaminase. Unfortunately, there is no new information related to the possible clinical applications of zebularine. Although many new inhibitors of DNMT have been identified, none of them can so far replace azacytidine, decitabine and, to a lesser degree, zebularine. This review summarizes the current data and knowledge about azacytidine, decitabine and zebularine, and their role in present and possible future epigenetic cancer therapy. We also discuss the molecular modes of action of these agents with consideration of their different toxicities and demethylation profiles, reflecting their complex and partially overlapping biological effects.
authors.affiliation: Department of Pharmacology, National Medicines Institute, Chelmska Street 30/34, 00-725 Warsaw, Poland. sylwia.flis@yahoo.pl
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gnyszka
authors.forename: Zenon
authors.initials: Z
authors.lastname: Jastrzebski
authors.forename: Sylwia
authors.initials: S
authors.lastname: Flis
mesh_terms: D001372:Aza Compounds / Q000494:pharmacology / Q000627:therapeutic use; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics
chemical_list: D001372:Aza Compounds; D004791:Enzyme Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: DNA methylation; DNMT inhibitors; Epigenetics; cancer therapy; review