Proper sequencing of HDAC inhibitors with anthracyclines will likely be important to the success of these combinations. Pretreatment with HDAC inhibitors prior to anthracycline exposure may provide synergistic effects as well by increasing nuclear DNA exposure to anthracycline. In cultured MCF-7 breast cancer cells, treatment with the HDAC inhibitor vorinostat leads to chromatin decondensation which is maximal after 48 hours of HDAC inhibitor treatment. In this system, co-administration of vorinostat and epirubicin did not lead to increased apoptosis whereas 48 hour pre-incubation with vorinostat led to synergistic increases in apoptosis associated with increased nuclear accumulation of epirubicin and increased DNA damage. In AML, maximal epigenetic effects appear to occur at about 48 hours after HDAC inhibitor exposure as well.