Previous studies have shown that
prostaglandin E(2) (
PGE(2)) is involved in intestinal
carcinogenesis through its binding to the
PGE(2) receptor subtypes EP(1) and EP(4) and activation of downstream pathways.
ONO-8711 and ONO-AE2-227,
prostaglandin E receptor subtype EP(1)- and EP(4)-selective antagonists, respectively, are known to suppress formation of
intestinal polyps in
adenomatous polyposis coli gene-deficient mice. The present study was designed to investigate the combined effects of EP(1) and EP(4) antagonists on spontaneous
polyp formation in APC1309 mice in order to determine the contribution of each receptor to intestinal
tumorigenesis. APC1309 mice were treated with 400 ppm of
ONO-8711 alone, 400 ppm of ONO-AE2-227 alone or both in combination in the diet for 6 weeks. The mean area of
polyps found in the intestine, calculated as the longer diameter x the shorter diameter x pi, was reduced by 12%, 43% (P < 0.01) and 56% (P < 0.01) of the mean control value (8.8 mm(2)) in the
ONO-8711 alone, ONO-AE2-227 alone and combination treatment groups, respectively, suggesting clear additive effects of the combination. The same additive tendency for suppression was also observed with respect to the numbers of
polyps in the intestine.
Polyp size reduction was more remarkable with the EP(4) antagonist, while the number reduction was more pronounced with the EP(1) antagonist. Our results indicate that EP(1) and EP(4) may have separate intrinsic roles and, to some extent, contribute to
polyp formation independently. Thus, combination treatment has potential for the
chemoprevention of colon
carcinogenesis.