Decitabine--bedside to bench.
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Oki Y, Aoki E, Issa JP
Decitabine--bedside to bench.
Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4.
- PubMed ID
- 17023173 [ View in PubMed]
- Abstract
PURPOSE OF THE REVIEW: Epigenetic changes marked by DNA methylation are known to contribute to the malignant transformation of cells by silencing critical genes. Decitabine inhibits DNA methyltransferase and has shown therapeutic effects in patients with hematologic malignancies. However, the connection between the clinical activity of decitabine and its demethylating activity is not clear. Herein, we summarize the results of recent clinical trials of decitabine in hematologic malignancies, and review the translational research into decitabine's mechanism of clinical activity. RECENT FINDINGS: Low-dose decitabine has been studied recently in multiple clinical trials and has been shown to be effective for treatment of myelodysplastic syndromes. Correlative laboratory studies of clinical trials have shown that decitabine induces global hypomethylation as well as hypomethylation of gene-specific promoters and activation of gene expression. Past a given threshold, induction of higher degrees of hypomethylation is not directly associated with a better clinical outcome. Moreover, studies have suggested that patients with promoter hypermethylation of p15(INK4B) at baseline have paradoxically a lower chance of achieving response than those without hypermethylation. Furthermore, several other genes activated by decitabine were independent of hypomethylation in the promoter regions. CONCLUSION: While at least part of decitabine's activity is through induction of hypomethylation and reactivation of critical genes, mechanisms independent from hypomethylation are also important for decitabine's antitumor activity.
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 Decitabine DNA (cytosine-5)-methyltransferase 3A Protein Humans UnknownInhibitorDetails Decitabine DNA (cytosine-5)-methyltransferase 3B Protein Humans UnknownInhibitorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Decitabine Deoxycytidine kinase Protein Humans YesSubstrateDetails Decitabine Nucleoside diphosphokinase (Protein Group) Protein group Humans YesSubstrateDetails Decitabine UMP-CMP kinase Protein Humans YesSubstrateDetails - Drug Reactions
Reaction Details