Document Detail

Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model.
MedLine Citation:
PMID:  18606719     Owner:  NLM     Status:  MEDLINE    
To ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the antitumor effects of trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TSA and vorinostat both displayed strong antitumor activities in 50% of NSCLC cell lines, suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P < 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified National Cancer Institute program. In addition, pathway analysis was done with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the support vector machine model was validated by an additional nine cell lines, resulting in a prediction value of 100% with respect to determining response to TSA and vorinostat. Our results suggested that (a) HDAC inhibitors may be promising anticancer drugs to NSCLC and (b) the nine-gene classifier is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients.
Akihiko Miyanaga; Akihiko Gemma; Rintaro Noro; Kiyoko Kataoka; Kuniko Matsuda; Michiya Nara; Tetsuya Okano; Masahiro Seike; Akinobu Yoshimura; Akiko Kawakami; Haruka Uesaka; Hiroki Nakae; Shoji Kudoh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-07
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  7     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-22     Completed Date:  2008-09-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1923-30     Citation Subset:  IM    
Department of Internal Medicine, Division of Pulmonary Medicine, Infectious Diseases and Oncology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / enzymology*,  genetics,  pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Enzyme Inhibitors / pharmacology*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Genes, Neoplasm
Histone Deacetylase Inhibitors*
Hydroxamic Acids / pharmacology
Inhibitory Concentration 50
Lung Neoplasms / enzymology*,  genetics,  pathology
Models, Biological*
Reproducibility of Results
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 58880-19-6/trichostatin A

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