Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay

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Title
Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay
Author(s)
J C Kim; D D Kim; Y M Lee; T W Kim; D H Cho; M B Kim; S G Ro; Seon-Young KimYong Sung Kim; J S Lee
Bibliographic Citation
International Journal of Colorectal Disease, vol. 24, no. 2, pp. 209-218
Publication Year
2009
Abstract
Background and aims: This study was to evaluate the efficacy of histone deacetylase (HDAC) inhibitors in colorectal cancer together with other established regimens. Materials and methods: Chemosensitivities of 114 colorectal cancer patients to established regimens (fluorouracil (5-FU with leucovorin (FL), capecitabine, FL with irinotecan (FLIRI), and FL with oxaliplatin (FLOX)) as well as five hydroxamic acid derivatives (suberoylanilide hydroxamic acid, PXD101, and three novel candidates of CG-1, CG-2, and CG-3) were comparatively evaluated using the histoculture drug response assay. Results: The chemosensitivity with established regimens was between 34.2% and 52.6%, when the cutoff value of the inhibition ratio was set at 30%, and between 54.5% and 84.1% with HDAC inhibitors. All HDAC inhibitors displayed synergistic effects in combination with established regimens of FLOX and FLIRI (P ≤ 0.0001 - 0.002). Advanced T- and N-category tumors and patients with synchronous adenoma displayed higher chemosensitivity to CG-3, CG-2, and CG-1, respectively, on a multivariate analysis (P = 0.023, 0.044, and 0.045, respectively). Tumors with mismatch repair defects were closely correlated with chemosensitivities to combined regimens of PDX101 with FLOX and FLIRI (P = 0.044 and 0.048, respectively). Conclusions: Our findings firstly demonstrated the chemo-responsiveness of colorectal cancers to HDAC inhibitors with therapeutic efficacy comparable to the established regimens. Additionally, tumor growth and heredity were significantly associated with specific regimens, supporting their possible role as chemosensitive predictors.
Keyword
ChemosensitivityColorectal adenocarcinomasHistoculture drug response assay (HDRA)Histone deacetylase inhibitor
ISSN
0179-1958
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s00384-008-0590-1
Type
Article
Appears in Collections:
Korea Bioinformation Center > 1. Journal Articles
Division of Biomedical Research > Genome Editing Research Center > 1. Journal Articles
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