Decitabine--bedside to bench.

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.

• Authors: Yasuhiro Oki, Etsuko Aoki, Jean-Pierre J Issa
• Journal: Critical reviews in oncology/hematology (Crit Rev Oncol Hematol) Vol. 61 Issue 2 Pg. 140-52 (Feb 2007) ISSN: 1040-8428 [Print] Netherlands
• PMID: 17023173 (Publication Type: Journal Article, Review)

Chemical References

• Antimetabolites, Antineoplastic
• Enzyme Inhibitors
• Decitabine
• Methyltransferases
• Azacitidine

Topics

• Antimetabolites, Antineoplastic (pharmacology, therapeutic use)
• Azacitidine (analogs & derivatives, pharmacology, therapeutic use)
• DNA Methylation (drug effects)
• Decitabine
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Gene Silencing (drug effects)
• Humans
• Methyltransferases (antagonists & inhibitors)
• Molecular Structure
• Neoplasms (drug therapy, genetics)