chemical structures have not been discussed beyond the purpose of the current study. Briefly, these compounds are hydroxamic acid derivatives similar to SAHA and SGLT PXD101 but include linkers and hydrophobic domains via optimization of novel scaffolds, distinct from the known HDAC inhibitors. SAHA has several protein targets whose structures and functions are altered by acetylation, including chromatin associated histones, nonhistone gene transcription factors, and proteins involved in the regulation of cell proliferation, migration, and death . PXD101, a highly potent HDAC inhibitor, blocks the proliferation of tumor cell lines at low concentrations and HDAC enzyme activity, as confirmed in our study . To our knowledge, this study presents the first evaluation of drug responses of colorectal cancers to HDAC inhibitors in comparison with established regimens.
HDRA is based on tissue culture for a Erlotinib relatively short period, which has several advantages over other cell culture based assays . The short duration of the experiment may minimize the variable effects of cell proliferation and death over the assay period. On the other hand, tissue cultures preserve cell to cell or cell to stroma interactions and maintain intact cyto architecture in vivo, possibly compromising drug accessibility. HDRA utilizes MTT as a quantitative end point, which involves the evaluation of total tumor cell viability, unlike clonogenic and radioactive assays that only measure dividing cells effectively . Thus, MTT based HDRA is a valuable tool to assess chemosensitivity to novel drugs and their mode of interaction between established and novel drugs, as in our study.
We employed patient tumors rather than established cell lines. Previous reports show considerable differences in chemosensitivity between the two sample types . The cut off values of IR are defined as 30% dermatology to 60%, according to the study design and tested drugs . We used the lowest level of IR , since our drug concentrations were in the low range, compared with previous investigations. We recorded successful assay rates of greater than 98%, whereby HDRA was efficiently performed on nearly all patient samples. Successful assay with different cancers and regimens were recorded using HDRA , which were higher than those obtained with other chemosensitivity assays .
HDRA is a useful in vitro drug sensitivity assay owing to significant correlations between the inhibitory indices obtained with this method and clinical outcomes after chemotherapy . However, all in vitro assays have several limitations with regard to reproducibility and tumor cell heterogeneity, along with few clinical correlation outcomes on a randomized control trial basis. Chemosensitivity mainly depends on the cut off values for IR, regimens and their concentrations, and PK and PD profiles. Our response rates were similar to or slightly higher than those reported in clinical studies using the same regimens . Tumor growth IR was highest for FLOX, followed by FL, FLIRI, 5 FU and capecitabine , consistent with data from previous clinical trials. A combination of 5 FU with leucovorin has been the standard chemotherapy for stage III colon cancer since 1996 . The well known study by the de Gramont group presented a significantly higher response rate .