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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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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.

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Acknowledgements

This study was supported by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A062254). We are grateful to U.S. Shin and S.N. Yoon for the arrangement of tissue samples and the clinical database, and J.K. Park and O.S. Shin for technical advice and support.

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Authors and Affiliations

  1. Department of Surgery and Institute of Innovative Cancer Research, University of Ulsan College of Medicine and Asan Medical Center, 388-1 Poongnap-2-Dong Songpa-Ku, Seoul, 138-736, Republic of Korea

    Jin C. Kim, Dae D. Kim, Yoo M. Lee, Dong H. Cho, Moon B. Kim & Seong G. Ro

  2. Department of Internal Medicine and Institute of Innovative Cancer Research, University of Ulsan College of Medicine and Asan Medical Center, 388-1 Poongnap-2-Dong Songpa-Ku, Seoul, 138-736, Republic of Korea

    Tae W. Kim & Jung S. Lee

  3. Medical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology, 52 Eoeun-Dong Yuseong-Ku, Daejeon, 305-806, Republic of Korea

    Seon Y. Kim & Yong S. Kim

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  1. Jin C. Kim
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Correspondence to Jin C. Kim.

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Kim, J.C., Kim, D.D., Lee, Y.M. et al. Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay. Int J Colorectal Dis 24, 209–218 (2009). https://doi.org/10.1007/s00384-008-0590-1

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