Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett's esophagus.
OBJECTIVE
Carcinogenesis in Barrett's esophagus (BE) is associated with an increased expression of cyclooxygenase (COX) 2. However, there has been no direct evidence that inhibition of COX-2 prevents cancer in BE. We studied the effect of MF-Tricyclic, a selective COX-2 inhibitor, on the development of BE and adenocarcinoma in a rat model.


METHODS
Four weeks after esophagojejunostomy, 105 Sprague-Dawley rats were randomized to a chow containing MF-Tricyclic or Sulindac, or a placebo. Ninety-six (92%) rats completed the study and were sacrificed at 28 +/- 2 weeks. The animals were assessed for the presence of cancer, tumor volume, BE, degree of inflammation, and COX-2 expression and activity.


RESULTS
MF-Tricyclic and Sulindac reduced the relative risk of development of esophageal cancer by 55% (95% confidence interval [CI] = 43%-66%, P < 0.008) and by 79% (95% CI = 68%-87%, P < 0.001), respectively, compared with controls. No significant differences were noted in the risk of esophageal cancer between the MF-Tricyclic and the Sulindac group (P = 0.34). The median tumor volume was not significantly different among the 3 groups (P = 0.081). Moderate to severe degree of inflammation was significantly more common (P = 0.005) in the control compared with the MF-Tricyclic and the Sulindac group; however, the prevalence of BE was not significantly different between groups (P = 0.98). Rats in the control group had higher tissue PGE2 level compared with the MF-Tricyclic and Sulindac groups (P = 0.038).


CONCLUSIONS
Selective and nonselective COX-2 inhibitors can inhibit inflammation, COX-2 activity, and development of adenocarcinoma induced by reflux. This provides direct evidence that COX-2 inhibitors may have chemopreventive potential in BE.
Buttar
Navtej S
NS
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Graduate School of Medicine, Rochester, Minnesota, USA.
Wang
Kenneth K
KK
Leontovich
Olga
O
Westcott
Jay Y
JY
Pacifico
Rodney J
RJ
Anderson
Marlys A
MA
Krishnadath
Krishnawatie K
KK
Lutzke
Lori S
LS
Burgart
Lawrence J
LJ
D000230:Adenocarcinoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001471:Barrett Esophagus / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004941:Esophagitis / Q000150:complications / Q000473:pathology; D005663:Furans / Q000097:blood / Q000494:pharmacology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D007783:Lactones / Q000097:blood / Q000494:pharmacology; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases