Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine.
Article Details
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Stresemann C, Lyko F
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.
- PubMed ID
- 18425818 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Decitabine DNA Nucleotide Humans YesOther/unknownDetails Decitabine DNA (cytosine-5)-methyltransferase 1 Protein Humans YesInhibitorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Decitabine Cytidine deaminase Protein Humans NoSubstrateDetails Decitabine Deoxycytidine kinase Protein Humans YesSubstrateDetails