Celecoxib inhibits growth of tumors in a syngeneic rat liver metastases model for colorectal cancer.
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer in cyclooxygenase-2 (COX-2) overexpressing colorectal cancers. The present study was designed to evaluate the inhibitory effects of the COX-2 inhibitor celecoxib on the growth of colorectal cancer liver metastases in a syngeneic rat model, CC531.


METHODS
The effects of celecoxib on cell viability in vitro were evaluated by treatment of CC531 tumor cell cultures with celecoxib. In vivo, Wag/Rij rats were inoculated with CC531 tumor cells at two sites in the liver and treated with celecoxib starting one week before, or directly after tumor inoculation. Control rats were inoculated without treatment. Three weeks after tumor inoculation rats were sacrificed. Tumor size, immune cell infiltration, caspase-3 activity, PGE(2) and celecoxib levels were determined.


RESULTS
CC531 tumors did not show COX-2 expression. Tumor growth was significantly inhibited by celecoxib treatment in a dose dependent manner. Immune cell infiltration was decreased after celecoxib treatment, indicating that the immune system was not involved in preventing tumor growth. Tumor caspase-3 levels were only significantly increased if treatment was started before tumor inoculation. Celecoxib serum concentration starting at 0.84 microg/ml significantly inhibited the outgrowth of CC531 liver tumors. In contrast, in vitro concentrations of celecoxib of at least 12 microg/ml were needed to affect tumor cell viability.


CONCLUSIONS
These results suggest that the inhibitory effects of celecoxib on tumor growth are not by direct cytotoxicity, but by creating an unfavorable environment for tumor growth.
de Heer
Pieter
P
Department of Surgery, K6-R, Leiden University Medical Center, P.O. Box 9600, 2300, RC, Leiden, The Netherlands.
Sandel
Maro H
MH
Guertens
Gunther
G
de Boeck
Gert
G
Koudijs
Margaretha M
MM
Nagelkerke
J Fred
JF
Junggeburt
Jan M C
JM
de Bruijn
Ernst A
EA
van de Velde
Cornelis J H
CJ
Kuppen
Peter J K
PJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary*; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D000068579:Celecoxib; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020556:Neutrophil Infiltration / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis; D011720:Pyrazoles / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D053148:Caspase 3; D000068579:Celecoxib; D015232:Dinoprostone