Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice.
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.
Kitamura
Tomohiro
T
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Itoh
Masaki
M
Noda
Tetsuo
T
Tani
Kousuke
K
Kobayashi
Michiyoshi
M
Maruyama
Takayuki
T
Kobayashi
Kaoru
K
Ohuchida
Shuichi
S
Sugimura
Takashi
T
Wakabayashi
Keiji
K
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002208:Caproates / Q000494:pharmacology*; D005260:Female; D017353:Gene Deletion; D017491:Genes, APC; D005838:Genotype; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
D001643:Bridged Bicyclo Compounds; D002208:Caproates; C122148:ONO 8711; C545636:Ptger1 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype