Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis

Kitamura, Toshiya; Kawamori, Toshihiko; Uchiya, Naoaki; Itoh, Masaki; Noda, Tetsuo; Matsuura, Mamoru; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1093/carcin/23.9.1463

Cited by 71 publications

(56 citation statements)

References 13 publications

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“…C57BL/6-Apc Min/+ mice (Apc Min/+ mice) were purchased from The Jackson Laboratory. Apc 1309 and Apc Min/+ mice offspring were genotyped according to the method previously described (27,28) and recommendations of The Jackson Laboratory, respectively. Male mice were randomized into experimental and control groups and were fed standard laboratory chow and tap water ad libitum.…”

Section: Animalsmentioning

confidence: 99%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

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Insulin-like growth factors (IGF-I and IGF-II) play important roles in intestinal tumorigenesis. To investigate the effectiveness of IGF-targeting strategies, we conducted an in vivo study using anti-mouse neutralizing antibodies IGF-I (KM3168) and IGF-II (KM1468). Six-and 10-week-old Apc +/− mice were given KM3168 and/or KM1468 i.p. at two doses (0.01 or 0.1 μg/g weight) once or twice weekly for 4 weeks. To clarify the source of IGFs in vivo, we evaluated the expression levels of IGFs in the liver, normal small intestine, and polyps of the small intestine of Apc +/− mice. The phosphorylation status of IGF signalrelated molecules was examined using immunostaining to understand the mechanism underlying the effects of IGF-neutralizing antibody. The plasma half-life was 168 for KM3168 and 85 hours for KM1468. In two lineages of Apc +/− mice (Apc 1309 and Apc Min/+ ), a low dose (0.01 μg/g weight) of KM3168 and KM1468 significantly reduced the number of polyps when given once and twice weekly, respectively. Combined administration of the effective dose of each antibody had an additive effect. The liver was the main source of IGF-I, whereas the polyps of the small intestine and normal small intestine were the main source of IGF-II. IGF-neutralizing antibodies decreased the phosphorylation of IGF type 1 receptor and inhibited the signal transduction of the Akt pathway. These results suggest that IGF-I and IGF-II play important roles in polyp formation in Apc +/− mice and that specific antibodies to IGF-I and IGF-II may be promising antitumor agents. Mol Cancer Ther; 9(2); 419-28. ©2010 AACR.

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Section: Animalsmentioning

confidence: 99%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

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“…14 Moreover, we recently demonstrated that mofezolac, a COX-1 selective inhibitor, suppressed the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACFs), putative preneoplastic lesions in F344 rats and intestinal polyp development in mice with a truncated Apc gene at codon 1309 (APC1309 mice). 15 It should be noted that prostaglandin E 2 (PGE 2 ) levels were increased in intestinal polyps in Min mice compared with surrounding normal tissue, and genetic disruption of the COX-1 gene, as well as the COX-2 gene, indicated that both isoforms contributed to PGE 2 production. 14 PGE 2 exerts its biologic actions through binding to the 4 specific membrane receptor subtypes EP 1 , EP 2 , EP 3 and EP 4 .…”

Section: Abstract: Apc Knockout Mice; Cox-1 Selective Inhibitor; Coxmentioning

confidence: 99%

“…15,23 Mice at 7 weeks of age were randomized into experimental and control groups. The animals were housed 2 or 3 to a plastic cage in a holding room controlled at 24 Ϯ 2°C and at 55% relative humidity with a 12/12-hr light-dark cycle.…”

Section: Animals and Chemicalsmentioning

confidence: 99%

“…Six hundred ppm mofezolac and 400 ppm nimesulide were selected because they were previously reported to suppress polyp development in the mice. 15 We also set half-dose levels to avoid possible additive side effects in the combination treatment groups. Ten ppm indomethacin was selected as the maximum tolerated dose level based on preliminary study in our laboratory (data not shown).…”

Section: Experimental Protocolmentioning

confidence: 99%

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Combined effects of cyclooxygenase‐1 and cyclooxygenase‐2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice

Kitamura¹,

Itoh

Noda

et al. 2004

Intl Journal of Cancer

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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 ...

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“…The mofezolac ([3,4-di(4-methoxyphenyl)-5-isoxazolyl] acetic acid) (Kitamura et al, 2002) was a gift from Yoshitomi Pharmaceutical Corporation. (Tokyo, Japan).…”

Section: Chemicals and Other Materialsmentioning

confidence: 99%

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

Yoshida

Aoki

Hayashi

et al. 2003

Laboratory Investigation

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SUMMARY:Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis and is COX-2 and vascular endothelial growth factor (VEGF) dependent. In this model, VEGF expression was down-regulated by selective COX-2 inhibition with NS-398. To find out the involvement of COX-2/VEGF pathway in tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or Lewis lung carcinoma cells. Daily oral administration of NS-398 or of aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial tumors with extensive angiogenesis markedly suppressed by aspirin and COX-2 inhibitors NS-398 and JTE522, but not by mofezolac, an inhibitor of constitutive COX-1. Tumor-associated angiogenesis was also significantly suppressed by a neutralizing antibody against VEGF. S-180 tumor growth in the subcutaneous tissues was also suppressed by aspirin, COX-2 selective inhibitors, and the VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/VEGF-dependent pathway was effective in tumor-associated angiogenesis, tumor growth, and tumor metastasis. (Lab Invest 2003, 83:1385-1394.

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Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis

Cited by 71 publications

References 13 publications

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Combined effects of cyclooxygenase‐1 and cyclooxygenase‐2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

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