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Cyclooxygenase (COX)-2, one enzyme isoform responsible for producing prostanoids from arachidonic acid, contributes to colon carcinogenesis. Recently, genetic disruption of COX-1, the other isoform, was shown to decrease the number of intestinal polyps and prostaglandin E(2) levels in intestinal mucosa, like the case with COX-2 gene disruption, in Min mice. We therefore investigated whether a COX-1 selective inhibitor, mofezolac, suppresses intestinal carcinogenesis in rodents. F344 male rats, receiving azoxymethane (AOM, 15 mg/kg body wt) s.c. injections at 5 and 6 weeks of age, were fed a diet containing 600 or 1200 p.p.m. mofezolac for 4 weeks. The number of aberrant crypt foci (ACFs) per rat and the bromodeoxyuridine labeling index of the crypt epithelium were dose-dependently decreased by administration of mofezolac, the value for the former at 1200 p.p.m. being 60% of control value. When Apc gene knockout mice (APC1309 mice) were given 600 or 1200 p.p.m. mofezolac in their diet for 8 weeks, the numbers of intestinal polyps were also dose-dependently decreased, with reduction to 59% of that in the control diet group at the higher dose. Nimesulide, a COX-2 selective inhibitor used as positive control, showed similar suppressive effects on the development of ACFs in AOM-treated rats and polyps in Apc gene knockout mice. The data indicate that both COX-1 and COX-2 can contribute to intestinal tumorigenesis.

As with cyclooxygenase (COX)-2, genetic disruption of COX-1 gene or pharmacologic inhibition of its activity has been shown to decrease the number of intestinal polyps in Apc gene-deficient mice. The present study was designed to investigate the combined effects of COX-1 and COX-2 selective inhibitors on spontaneous polyp formation in APC1309 female mice. The animals were treated with 300 or 600 ppm mofezolac (a COX-1 selective inhibitor) alone, 200 or 400 ppm nimesulide (a COX-2 selective inhibitor) alone, 300 ppm mofezolac plus 200 ppm nimesulide, 600 ppm mofezolac plus 400 ppm nimesulide, or 10 ppm indomethacin (a dual-COX inhibitor) in the diet from 7 weeks of age for 4 weeks. Percentage inhibition of polyp area in the intestine was 17% with 600 ppm mofezolac alone and 25% with 400 ppm nimesulide alone, their sum of 42% being almost equal to the 37% observed for the combination treatment. Administration of 300 ppm mofezolac plus 200 ppm nimesulide also significantly decreased polyp area in the intestine by 30%. Moreover, the numbers of polyps more than 2.5 mm in diameter were markedly decreased by combined treatment of both COX inhibitors. With 10 ppm indomethacin, the dual inhibitor, polyp area was also clearly reduced by 46%. Our results indicate that COX-1 and COX-2 may to some extent contribute to polyp formation independently and inhibitor combination treatment thus has particular potential for chemoprevention of colon carcinogenesis. © 2004 Wiley-Liss, Inc. Key words: Apc knockout mice; COX-1 selective inhibitor; COX-2 selective inhibitor; intestinal tumorigenesis; combined effectLong-term use of aspirin, a nonsteroidal antiinflammatory drug (NSAID), has been found in the epidemiologic studies to result in reduction in mortality rate from colorectal cancer. 1,2 Furthermore, treatment with NSAIDs suppresses the development of chemical carcinogen-induced colon cancers in experimental animals. 3,4 Similarly, decrease has been achieved with such agents regarding intestinal polyps in patients with familial adenomatous polyposis (FAP) [5][6][7] and in an animal model of the disease, mutant mice with a truncated adenomatous polyposis coli (Apc) gene. 8 NSAIDs block arachidonic acid metabolism by inhibiting cyclooxygenase (COX) activity and thus reducing levels of prostaglandins, which affect cell proliferation, tumor growth, apoptosis and immune responsiveness. Two enzyme isoforms of COX are known, referred to as COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays a role in various physiologic functions, while COX-2 is transiently inducible by stimuli such as cytokines, growth factors and hormones and contributes to inflammation. 9 By using COX-2 selective inhibitors or mutant mice featuring disruption of the gene encoding this enzyme, relevance to carcinogenesis in various organs, including the colon, has been shown. 10 -13 Possible involvement of COX-1 in colon carcinogenesis has also been reported. Genetic disruption of the COX-1 gene decreased the number of intestinal polyps in ...

These results suggest that the anti-arthritic effect of FTY720 in this adjuvant-induced arthritic model was more potent than those of cyclosporin A and tacrolimus. FTY720 administered on days 6 to 10 showed the inhibitory effect on the bone destruction and hindpaw edema. FTY720 may be effective in the treatment of rheumatoid arthritis.

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