Six (or more) drugs in search of a mechanism: DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes.
The clinical activity of the DNA methyltransferase inhibitors 5-azacitidine and 2'-deoxy-5-azacytidine in myelodysplastic syndromes (MDS) suggests that epigenetic modulation of gene transcription may play an important pathogenetic role in the development and expression of these diseases. Approximately 50% of patients treated with these compounds experience hematologic improvement, making these the most active single agents for unselected patients with MDS. Responses include complete and partial hematologic responses. Two randomized trials have shown that the use of these drugs significantly alters the natural history of MDS compared with supportive care. Histone deacetylase inhibitors, which may also impact the expression of genes through epigenetic mechanisms, seem to have measurable activity in MDS in preliminary studies. Histone deacetylase inhibitors are most likely used in combination with other agents, including DNA methyltransferase inhibitors. Despite the clinical activity of these classes of drugs, there is no conclusive evidence that their clinical activity is attributable to their impact on the epigenome. Such information will be critical in the development of more effective congeners and drug combinations in ongoing attempts to improve the outcome of patients with MDS.
Gore
Steven D
SD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21231, USA. Steven.Gore@Jhu.edu
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D015254:DNA Modification Methylases