Targeting DNA methylation.

Abstract

Two nucleoside inhibitors of DNA methylation, azacitidine and decitabine, are now standard of care for the treatment of the myelodysplastic syndrome, a deadly form of leukemia. These old drugs, developed as cytotoxic agents and nearly abandoned decades ago were resurrected by the renewed interest in DNA methylation. They have now provided proof of principle for epigenetic therapy, the final chapter in the long saga to provide legitimacy to the field of epigenetics in cancer. But challenges remain; we don't understand precisely how or why the drugs work or stop working after an initial response. Extending these promising findings to solid tumors faces substantial hurdles from drug uptake to clinical trial design. We do not know yet how to select patients for this therapy and how to move it from life extension to cure. The epigenetic potential of DNA methylation inhibitors may be limited by other epigenetic mechanisms that are also worth exploring as therapeutic targets. But the idea of stably changing gene expression in vivo has transformative potential in cancer therapy and beyond.

• Authors: Jean-Pierre J Issa, Hagop M Kantarjian
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 12 Pg. 3938-46 (Jun 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19509174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Antimetabolites, Antineoplastic (therapeutic use)
• Azacitidine (analogs & derivatives, chemistry, therapeutic use)
• Clinical Trials as Topic
• DNA Methylation (drug effects)
• DNA Modification Methylases (antagonists & inhibitors)
• Decitabine
• Epigenesis, Genetic (drug effects)
• Humans
• Myelodysplastic Syndromes (drug therapy, genetics)
• Neoplasms (drug therapy, genetics)