In vitro evaluation of histone deacetylase inhibitors as combination agents for colorectal cancer.
BACKGROUND
Our primary aim was to evaluate the additive efficacy of histone deacetylase inhibitors (HDACIs) in established treatment regimens for colorectal cancer in concurrence with identifying the clinicopathological markers significantly associated with tumor responsiveness.


METHODS
The chemosensitivities of 125 colorectal carcinomas to established regimens [FLOX (5-FU + leucovorin + oxaliplatin) and FLIRI (5-FU + leucovorin + irinotecan)], two biologically targeted drugs (avastin and erbitux), and two hydroxamic acid derivatives (vorinostat, SAHA(R), and a novel candidate, CG2) were comparatively evaluated using an in vitro tumor response assay.


RESULTS
The response rates of tumors (inhibition rate > or =30%) were significantly greater for FLOX and combinations (55.2-68%) compared to FLIRI and combinations (44-63.2%) (p=0.001 to 0.048), except in the case of the CG2 combination. The additive effects of HDACIs on the respective established regimens were considerably greater for non-responsive tumors (64.3-80%) than responsive tumors (32.7-45%) (p< or =0.0001 to 0.008). A number of biological parameters, including less advanced tumors and p53 overexpression, were significantly associated with additive chemosensitivity to HDACIs in combination with FLOX and FLIRI in multivariate analyses (p< or =0.001 to 0.023). Expanding tumor growth, diffuse cytoplasmic carcinoembryonic antigen (CEA) expression and synchronous adenoma were associated with combination regimens with targeted drugs (p=0.013 to 0.032).


CONCLUSIONS
Our findings show additive chemoresponsiveness of colorectal tumors to HDAC inhibitors in combination with established regimens. The significant parameters associated with combination regimens of targeted drugs and HDACIs may be applied as effective chemosensitive markers in future clinical trials.
Kim
Jin C
JC
Department of Surgery, University of Ulsan College of Medicine, 388-1 Poongnap-2-Dong Songpa-Ku, Seoul 138-736, Korea. jckim@amc.seoul.kr
Shin
Eui S
ES
Kim
Chan W
CW
Roh
Seon A
SA
Cho
Dong H
DH
Na
Young S
YS
Kim
Tae W
TW
Kim
Moon B
MB
Hyun
Young L
YL
Ro
Seonggu
S
Kim
Seon Y
SY
Kim
Yong S
YS
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors