Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine

Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607.


The cytosine analogues 5-azacytosine (azacytidine) and 2'-deoxy-5-azacytidine (decitabine) are the currently most advanced drugs for epigenetic cancer therapies. These compounds function as DNA methyltransferase inhibitors and have shown substantial potency in reactivating epigenetically silenced tumor suppressor genes in vitro. However, it has been difficult to define the mode of action of these drugs in patients and it appears that clinical responses are influenced both by epigenetic alterations and by apoptosis induction. To maximize the clinical efficacy of azacytidine and decitabine it will be important to understand the molecular changes induced by these drugs. In this review, we examine the pharmacological properties of azanucleosides and their interactions with various cellular pathways. Because azacytidine and decitabine are prodrugs, an understanding of the cellular mechanisms mediating transmembrane transport and metabolic activation will be critically important for optimizing patient responses. We also discuss the mechanism of DNA methyltransferase inhibition and emphasize the need for the identification of predictive biomarkers for the further advancement of epigenetic therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / pharmacology*
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacokinetics
  • Azacitidine / pharmacology*
  • DNA Methylation / drug effects*
  • DNA Modification Methylases / antagonists & inhibitors*
  • DNA Modification Methylases / metabolism*
  • Decitabine
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Epigenesis, Genetic / drug effects
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neoplasms / genetics*


  • Antimetabolites, Antineoplastic
  • Enzyme Inhibitors
  • Decitabine
  • DNA Modification Methylases
  • Azacitidine