In vitro basis for treatment with hypomethylating agents and histone deacetylase inhibitors: can epigenetic changes be used to monitor treatment?

Hematopoietic disorders such as myelodysplastic syndromes (MDS) show a high frequency of methylation of tumor suppressor genes. DNA methyltransferase (DNMT) inhibitors such as azacitidine and decitabine are used to target DNA methylation in MDS patients. Combining these drugs with histone deacetylase (HDAC) inhibitors in vitro resulted in synergistic tumor suppressor gene re-expression. Several phase I trials have examined methylation, gene expression and DNA damage as markers of clinical response to DNMT and HDAC inhibitors, with conflicting results. Trials are ongoing to investigate early methylation changes and DNA damage Markers to understand the mechanisms of these drugs and as potential predictors of clinical response. (C) 2009 Elsevier Ltd. All rights reserved.