Synergistic antitumor effects of celecoxib with 5-fluorouracil depend on IFN-gamma.
Cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colorectal cancers. For treatment of advanced cancers, combination of COX-2 inhibitors and chemotherapy has been attempted, but the results are still controversial. In the present study, the effects of the COX-2 inhibitor celecoxib on the anticancer potential of chemotherapy, and its mechanisms of action were investigated in point of the angiogenesis, using an advanced cancer model in mice. BALB/c mice were inoculated with colon 26 cells. After the allograft grew up to 5 mm in diameter, the animals received celecoxib, 5FU, or a combination of 5FU and celecoxib (5FU/celecoxib). After 21-days of the treatment, 5FU/celecoxib significantly inhibited the tumor growth and the tumor vessel density compared with the other groups. Celecoxib, 5FU or 5FU/celecoxib significantly suppressed the VEGF content in tumor tissues. 5FU/celecoxib also enhanced IFN-gamma levels in tumor tissue, which could be involved in the potent antitumor effects of 5FU/celecoxib. This hypothesis was proven, because in IFN-gamma knockout (IFN-gamma(-/-)) mice, the inhibitory effects of 5FU/celecoxib on angiogenesis and tumor growth were significantly impaired compared with that in wild type mice. These results suggest that celecoxib enhances the antitumor effect of 5FU against an advanced colon cancer model by suppressing angiogenesis. In addition to VEGF, IFN-gamma has pivotal roles in tumor suppression induced by celecoxib.
Irie
Takanobu
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Tsujii
Masahiko
M
Tsuji
Shingo
S
Yoshio
Toshiyuki
T
Ishii
Shuji
S
Shinzaki
Shinichiro
S
Egawa
Satoshi
S
Kakiuchi
Yoshimi
Y
Nishida
Tsutomu
T
Yasumaru
Masakazu
M
Iijima
Hideki
H
Murata
Hiroaki
H
Takehara
Tetsuo
T
Kawano
Sunao
S
Hayashi
Norio
N
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma; D000068579:Celecoxib; D005472:Fluorouracil