Piroxicam and Acarbose as Chemopreventive Agents for Spontaneous Intestinal Adenomas in APC Gene 1309 Knockout Mice

Quesada, Carlos F.; Kimata, Hiroyuki; Mori, Masayuki; Nishimura, Masahiko; Tsuneyoshi, Toshihiro; Baba, Shigeaki

doi:10.1111/j.1349-7006.1998.tb00576.x

Cited by 63 publications

(34 citation statements)

References 30 publications

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“…A study using transformed cells suggested an antineoplastic effect of acarbose treatment (18). In the APC gene knockout animal model, which develops multiple intestinal adenomas, acarbose had a regressive effect on the size of gastrointestinal adenomas but did not significantly decrease the number of colonic neoplasms (19). Previous smaller database studies investigating acarbose use and incident colorectal cancer have provided null results (10,20).…”

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confidence: 97%

Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients With Diabetes: A Nationwide, Population-Based Cohort Study

et al. 2015

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OBJECTIVEAcarbose, an a-glucosidase inhibitor, has been shown to have antineoplastic effects on colorectal cancer in biomarker studies. We assessed the association between acarbose use in patients with diabetes and incident colorectal cancer. RESEARCH DESIGN AND METHODSWe conducted a nationwide, population-based study using a large cohort with diabetes in the Taiwan National Health Insurance Research Database. Patients with newly diagnosed diabetes (n = 1,343,484) were enrolled between 1998 and 2010. One control subject not using acarbose was randomly selected for each subject using acarbose after matching for age, sex, diabetes onset, and comorbidities. Cox proportional hazards regression with a competing risks analysis was used to calculate the hazard ratios (HRs) and 95% CIs for the association between acarbose use and incident colorectal cancer for each eligible case-control pair (n = 199,296). RESULTSThere were 1,332 incident cases of colorectal cancer in the cohort with diabetes during the follow-up period of 1,487,136 person-years. The overall incidence rate was 89.6 cases per 100,000 person-years. Patients treated with acarbose had a 27% reduction in the risk of colorectal cancer compared with control subjects. The adjusted HRs were 0.73 (95% CI 0.63-0.83), 0.69 (0.59-0.82), and 0.46 (0.37-0.58) for patients using >0 to <90, 90 to 364, and ‡365 cumulative defined daily doses of acarbose, respectively, compared with subjects who did not use acarbose (P for trend < 0.001). CONCLUSIONSAcarbose use reduced the risk of incident colorectal cancer in patients with diabetes in a dose-dependent manner.Colorectal cancer is one of the most common cancers worldwide (1), causing an estimated 694,000 deaths in 2012 or 9.2% of all cancer-related deaths (2). Fecal occult blood screening and improved treatment in recent decades have reduced the annual global mortality of colorectal cancer (3). The incidence of colorectal cancer varies widely by geographic region and by degree of development. Although

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confidence: 97%

Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients With Diabetes: A Nationwide, Population-Based Cohort Study

et al. 2015

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“…Arachidonic acid is a substrate for cyclooxygenases 1 and 2 (COX-1 and COX-2), the primary enzymes responsible for prostaglandin biosynthesis (Herschmann, 1996;Murakami et al, 1998Murakami et al, , 1999Vane et al, 1998;Fourcade et al, 1995;Balsinde et al, 1998;Tisch®eld, 1997). COX-2 has been implicated genetically (Oshima et al, 1996) and pharmacologically (Yang et al, 1998;Shi et al, 1995;Piazza et al, 1995;Tsujii and Dubois, 1995;Tsujii et al, 1997;BeazerBarclay et al, 1996;Mahmoud et al, 1998;Boolbol et al, 1996;Jacoby et al, 1996;Taketo, 1998;Rao et al, 1995;Quesada et al, 1998;Nakatsugi et al, 1997) in the enhancement of intestinal tumorigenesis in both humans and rodents. Further, COX-2 is reported to be upregulated in both human colon cancer and in Min adenomas (Williams et al, 1996).…”

Section: Pla2g2a Lipid Metabolism and Intestinal Cancermentioning

confidence: 99%

The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64

et al. 2000

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The Mom1 (Modi®er of Min-1) region of distal chromosome 4 was identi®ed during a screen for polymorphic modi®ers of intestinal tumorigenesis in Apc Min/+ mice. Here, we demonstrate that the Mom1 AKR allele consists of two genetic components. These include the secretory phospholipase Pla2g2a, whose candidacy as a Mom1 resistance modi®er has now been tested with several transgenic lines. A second region, distal to Pla2g2a, has also been identi®ed using ®ne structure recombinants. Pla2g2a AKR transgenic mice demonstrate a modest resistance to tumorigenesis in the small intestine and a very robust resistance in the large intestine. Moreover, the tumor resistance in the colon of Pla2g2a AKR animals is dosage-dependent, a ®nding that is consistent with our observation that Pla2g2a is expressed in goblet cells. By contrast, mice carrying the distal Mom1 modi®er demonstrate a modest tumor resistance that is con®ned to the small intestine. Thus, the phenotypes of these two modi®er loci are complementary, both in their quantitative and regional eects. The additive eects and tight linkage of these modi®ers may have been necessary for the initial identi®cation of the Mom1 region. Oncogene (2000) 19, 3182 ± 3192.

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“…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%

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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Piroxicam and Acarbose as Chemopreventive Agents for Spontaneous Intestinal Adenomas in APC Gene 1309 Knockout Mice

Cited by 63 publications

References 30 publications

Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients With Diabetes: A Nationwide, Population-Based Cohort Study

Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients With Diabetes: A Nationwide, Population-Based Cohort Study

The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64

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

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