Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay.
OBJECTIVE
This study was to evaluate the efficacy of histone deacetylase (HDAC) inhibitors in colorectal cancer together with other established regimens.


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 < or = 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.
Kim
Jin C
JC
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. jckim@amc.seoul.kr
Kim
Dae D
DD
Lee
Yoo M
YM
Kim
Tae W
TW
Cho
Dong H
DH
Kim
Moon B
MB
Ro
Seong G
SG
Kim
Seon Y
SY
Kim
Yong S
YS
Lee
Jung S
JS
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors