Different cell kinetic changes in rat stomach cancer after treatment with celecoxib or indomethacin: implications on chemoprevention.
OBJECTIVE
Mechanisms underlying the chemopreventive effects of cyclooxygenase (COX) inhibitors remain elusive. We have previously shown that celecoxib but not indomethacin could prevent carcinogen-induced gastric cancer development in Wistar rats. This chemopreventive effect appeared to be independent of COX-2 and prostaglandin (PG) E2 suppression since the lowest PGE2 was obtained in indomethacin group. This study compared the cell kinetic changes in stomachs of rats after treatment with celecoxib (5, 10, 20 mg/(kg.d)) or indomethacin (3 mg/(kg.d)) to gain more insights into the chemopreventive mechanism.


METHODS
The apoptosis and proliferation indexes in gastric tumor, adjacent non-cancer tissues and normal gastric tissues were determined. Apoptosis was quantified by apoptotic nuclei counting and TUNEL, whereas proliferation was determined by Ki67 immunostaining.


RESULTS
Treatment with either celecoxib or indomethacin inhibited gastric tumor proliferation by more than 65% (P<0.02). However, celecoxib caused a dose-dependent increase in apoptosis (P<0.05) which was not seen in indomethacin-treated tumors (P = 0.54). The highest apoptosis to proliferation ratio was seen in tumors treated with celecoxib at 10 mg/(kg.d). Treatment with this dose of celecoxib was associated with the lowest incidence of gastric cancer development.


CONCLUSIONS
Our findings suggest that the difference in chemopreventive effects of indomethacin and celecoxib in this animal model of gastric carcinogenesis is largely due to the differential cell kinetic changes, which does not correlate with the degree of COX-2 and PG suppression.
Yu
Jun
J
Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Tang
Bao-Dong
BD
Leung
Wai-K
WK
To
Ka-Fai
KF
Bai
Alfa-Hc
AH
Zeng
Zhi-Rong
ZR
Ma
Po-Ki
PK
Go
Minnie-Yy
MY
Hu
Pin-Jin
PJ
Sung
Joseph-Jy
JJ
D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013274:Stomach Neoplasms / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D007213:Indomethacin