Histone deacetylase inhibitors in myelodysplastic syndrome

Histone deacetylase (HDAC) inhibitors are amongst the newer therapies being introduced in refractory, relapsed, and resistant disease. These agents are mechanism-based and their use is targeted to the diseased cell or tissue. HDACs are key enzymes in the regulation of gene expression. They maintain a dynamic equilibrium in the acetylation state of highly conserved lysine residues on histones by which they regulate chromatin remodeling and gene expression. Changes in growth and differentiation leading to malignancy appear to occur by alterations in transcriptional control and gene silencing. Histone acetylation and DNA methylation have been implicated in these aberrant phenotypes. Inhibitors of DNA methylation such as 5-azacytidine or 5-azadeoxycytidine have been able to reverse DNA methylation patterns and have shown promise in patient studies. Similarly, HDAC inhibitors block deacetylation function, causing cell cycle arrest, differentiation, and/or apoptosis of many tumors. Several HDAC inhibitors have exhibited potent antitumor activity in human xenograft models, suggesting their usefulness as novel cancer therapeutic agents. Several are currently in phase I/II clinical trials both in hematological malignancies and in solid tumors. Agents used initially, such as phenylbutyrate, are effective in millimolar concentrations. Newer agents are being developed and these are effective at much lower concentrations and are relatively less toxic. In particular, hydroxamic acid-based polar compounds and cyclic tetrapeptides have shown activity against cancers at well-tolerated doses.