Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor gamma agonist in an in vivo mouse model of spontaneous breast cancer.
OBJECTIVE
Activation of COX-2 and inhibition of PPARgamma have been observed in human and animal models of breast cancer. Both inhibition of COX-2 and activation of PPARgamma can inhibit proliferation of breast cancer cells in vitro. Here, we examine the effects of the COX-2 inhibitor celecoxib and the PPARgamma agonist N-(9-fluorenyl-methyloxycarbonyl)-l-leucine (F-L-Leu) on mouse breast tumor cells in vitro and in vivo.


METHODS
We created and characterized a mouse mammary adenocarcinoma cell (MMAC-1) line from C3 (1)-SV40 tumor antigen mice to study COX-2 and PPARgamma expression and response to celecoxib and F-L-Leu in vitro. To study the in vivo effects, C3 (1)-SV40 tumor antigen mice were given either control diet or diets containing three different concentrations of celecoxib and F-L-Leu as well as a combination of both agents. Mice were then followed for tumor formation up to 1 year.


RESULTS
MMAC-1 cells express both COX-2 and PPARgamma mRNA and exhibited cooperative growth inhibition with a combination of celecoxib and F-L-Leu. In mice, the median age of death due to mammary tumors was significantly delayed in celecoxib-treated animals at all three concentrations but was not significantly affected by F-L-Leu treatment alone. A combination of celecoxib and F-L-Leu was significantly more effective than celecoxib alone.


CONCLUSIONS
Our findings suggest that a combination of a COX-2 inhibitor and PPARgamma agonist can delay breast cancer in a mouse model and suggest that these agents should be studied in the context of human populations with high breast cancer risk.
Mustafa
Aladdin
A
Authors' Affiliation: Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Kruger
Warren D
WD
D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D018450:Disease Progression; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D047495:PPAR gamma / Q000819:agonists*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D047495:PPAR gamma; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib