The Histone Deacetylase Inhibitors (HDACIs) represent a new class of anticancer drugs showing preferential selectivity for cancer cells.While several mechanisms have been proposed to explain this selectivity, none can explain why other drugs utilizing these mechanisms do not show this preference.Inhibition of HDAC results in increased histone acetylation and consequently relaxes the chromatin structure.We have shown that trichostatin A (TSA) and vorinostat (SAHA), two HDACIs, can sensitize cancer cells to conventional anticancer drugs targeting chromatin DNA or enzymes acting on the DNA.This synergistic effect was observed in cancer cells but not in normal cells.We have now developed a new assay to measure chromatin accessibility at specific loci in cancer cells.Using a PCR-Stop assay coupled to RT-PCR we show that HDACIs increase the capacity of Topoisomerase 2 inhibitors to induce DNA strand breaks at Top2 targeted loci.Moreover, micrococcal nuclease digestions indicate that HDACIs can also increase accessibility of bulk chromatin in cells synchronized in either S or Go phases of the cell cycle.Understanding the intrinsic chromatin properties of cancer cells has important implication for the development of mechanism based clinical trials and of diagnostic tools to predict responsiveness to conventional anticancer drugs.