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. 1998 Apr;89(4):392–396. doi: 10.1111/j.1349-7006.1998.tb00576.x

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

Carlos F Quesada 1, Hiroyuki Kimata 1, Masayuki Mori 2, Masahiko Nishimura 2, Toshihiro Tsuneyoshi 3, Shozo Baba 1
PMCID: PMC5921824  PMID: 9617344

Abstract

The use of nonsteroidal anti‐inflammatory drugs has been suggested to have a chemopreventive effect against colon carcinoma, through the inhibition of cyclooxygenases 1 and 2, in patients with familial adenomatous polyposis and in animal models. Acarbose, an alpha‐glycosidase inhibitor, may also be chemopreventive. In order to examine the effects of these drugs we employed APC gene knockout mice randomized into 3 groups, one for treatment with piroxicam (0.05% concentration in drinking water), one for acarbose (0.04% concentration in food) and another for the control. After 14 weeks of treatment, mice were killed for quantitation of gastric and intestinal adenomas. Tumor multiplicity in the whole gastrointestinal tract decreased from 33.89±13.07 tumors/mouse in the control group to 17.05±7 tumors/mouse in the piroxicam‐treated group (P<0.001). The decrease in the acarbose‐treated group (29.68±12.86 tumors/mouse) was not significant (P>0.05). The number of tumors ≥3 mm in diameter was also quantified in all gastrointestinal segments. The number of such tumors in the piroxicam group was decreased to 0.56±1.2 tumors/mouse from the control value of 3.78±1.17 tumors/mouse (P<0.001), while in the acarbose‐treated group the number decreased to 2.36±1.7 tumors/mouse (P<0.01). Thus, piroxicam decreases the size and number of gastrointestinal adenomas in APC 1309 knockout mice, while acarbose decreases only the size.

Keywords: APC 1309 knockout mice, Chemoprevention, Piroxicam, Acarbose, Intestinal adenoma

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REFERENCES

  • 1. ) Rosenberg , L. , Palmer , J. R. , Zauber , A. G. , Warshauer , M. E. , Stolley , P. D. and Shapiro , S. A.Hypothesis: nonsteroidal anti‐inflammatory drugs reduce the incidence of large bowel cancer . J. Natl. Cancer Inst. , 83 , 355 – 358 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Thun , M. J. , Namboodiri , M. M. and Heath , C. W. , Jr.Aspirin use and reduced risk of fatal colon cancer . N. Engl. J. Med. , 325 , 1593 – 1596 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) DuBois , R. N. , Giardello , F. M. and Smalley , W. E.Non‐steroidal anti‐inflammatory drugs, eicosanoids, and colorectal cancer prevention . Gastroenterol. Clin. North Am. , 25 , 773 – 791 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Rao , C. V. , Rivenson , A. , Simi , B. , Zang , E. , Kelloff , G. , Steele , V. and Reddy , B. S.Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti‐inflammatory agent . Cancer Res. , 55 , 1464 – 1472 ( 1995. ). [PubMed] [Google Scholar]
  • 5. ) Moser , A. R. , Dove , W. F. , Roth , K. A. and Gordon , J. L.The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system . J. Cell Biol. , 116 , 1517 – 1526 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Jacoby , R. F. , Marshall , D. J. , Newton , M. A. , Novakovic , K. , Tutsh , K. , Cole , C. E. , Lubet , R. A. , Kellof , G. J. , Verma , A. , Moser , A. R. and Dove , W. F.Chemoprevention of spontaneous intestinal adenomas in the Apc min mouse model by the nonsteroidal anti‐inflammatory drug piroxicam . Cancer Res. , 56 , 710 – 714 ( 1996. ). [PubMed] [Google Scholar]
  • 7. ) Rigas , B. , Goldman , I. S. and Levine , L.Altered eicosanoid levels in human colon cancer . J. Lab. Clin. Med. , 122 , 518 – 523 ( 1993. ). [PubMed] [Google Scholar]
  • 8. ) Williams , C. W. and Dubois , R. N.Prostaglandin endoperoxide synthase: why two isoforms ? Am. J. Physiol. , 270 , 6393 – 6400 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Oshima , M. , Dinchuk , J. E. , Kargman , S. L. , Oshima , H. , Hancock , B. , Kwang , E. , Trzaskos , J. M. , Evans , J. and Taketo , M. M.Suppression of intestinal polyposis in APC knockout mice by inhibition of cyclooxygenase‐2 (COX‐2) . Cell , 87 , 803 – 09 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Dubois , R. N. , Radhika , A. , Reddy , B. S. and Entingh , A.Increased cyclooxygenase‐2 levels in carcinogen‐induced rat colonic tumors . Gastroenterology , 110 , 1259 – 1262 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Cybulsky , A. V. , Goodyer , P. R. , Cyr , M. D. and McTavish , A. J.Eicosanoids enhance epidermal growth factor receptor activation and proliferation in glomerular epithelial cells . Am. J. Physiol. , 262 , 639 – 646 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Denizot , Y. , Najid , A. and Rigaud , M.Effects of eicosanoid metabolism inhibitors on growth of a human gastric tumor cell line (HGT) . Cancer Lett. , 73 , 65 – 71 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Shapiro , A. C. , Wu , D. and Meydani , S. N.Eicosanoids derived from arachidonic and eicosapentaenoic acids inhibit T cell proliferative response . Prostaglandins , 45 , 229 – 240 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Shiff , S. J. , Qiao , L. , Tsai , L. L. and Rigas , B.Sulindac sulfide, an aspirin like compound, inhibits proliferation, causes cell cycle quiescence and induces apoptosis in HT‐29 colon adenocarcinoma cells . J. Clin. Invest. , 96 , 491 – 503 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Lombardino , J. G. and Wiseman , E. H.Piroxicam and other anti‐inflammatory oxicams . Med. Res. Rev. , 2 , 127 – 152 ( 1982. ). [Google Scholar]
  • 16. ) Pollard , M. and Luckert , P. H.Prolonged antitumor effect of indomethacin on autochthonous intestinal tumors in rats . J. Natl. Cancer Inst. , 70 , 1103 – 1105 ( 1983. ). [PubMed] [Google Scholar]
  • 17. ) Holt , P. R. , Atillasoy , E. , Lindenbaum , J. , Ho , S. B. , Lupton , J. R. , MacMahon , D. and Moss , S. F.Effects of acarbose on fecal nutrients, colonic pH, and short‐chain fatty acids and rectal proliferative indices . Metabolism , 45 , 1179 – 1187 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Thornton , J. R.High colonic pH promotes colorectal cancer . Lancet , i , 1081 – 1082 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Ito , M. , Miura , S. and Noda , T.Mouse model for familial adenomatous polyposis coli and APC gene . Protein Nucl. Acid Enzyme , 40 , 2035 – 2044 ( 1995. ) ( in Japanese ). [PubMed] [Google Scholar]
  • 20. ) Ito , M. , Shibata , H. and Noda , T.Mouse model for human cancer predisposition . Med. Today , 51 , 1153 – 1160 ( 1996. ) ( in Japanese ). [Google Scholar]
  • 21. ) Groden , J. , Thliveris , A. and Samoritz , W.Identification and characterization of the familial adenomatous polyposis . Cell , 66 , 589 – 600 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Kinzler , K. W. , Nilbert , M. C. and Su , L. K.Identification of FAP locus genes from chromosome 5q21 . Science , 253 , 661 – 665 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Powell , S. M. , Zilz , N. , Beazer‐Barclay , Y. , Bryan , T. M. , Hamilton , S. R. , Thibodeau , S. N. , Volgenstein , B. and Kinsler , K. W.APC mutations occur early during colorectal tumorigenesis . Nature , 359 , 235 – 237 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Giardello , F. M. , Hamilton , S. R. , Krush , A. J. , Piantadosi , S. , Hylind , L. M. , Celano , P. , Booker , S. V. , Robinson , C. R. and Offerhaus , G. J.Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis . N. Engl. J. Med. , 328 , 1313 – 1316 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Nicholls , R. J. , Springall , R. G. and Gallagher , P.Regression of rectal adenomas after colectomy and ileorectal anastomosis for familial adenomatous polyposis . Br. Med. J. , 296 , 1707 – 1708 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Moser , A. L. , Pitot , H. C. and Dove , W. F.A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse . Science , 247 , 322 – 324 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Vane , J. R.Towards a better aspirin . Nature , 367 , 215 – 216 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Eberhart , C. H. , Coffey , R. J. , Radhika , A. , Giardello , F. , Ferrenbach , S. and Dubois , R.Up‐regulation of cyclooxygenase‐2 gene expression in human colorectal adenomas and adenocarcinomas . Gastroenterology , 107 , 1183 – 1188 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Williams , C. S. , Luongo , C. , Radhika , A. , Zhang , T. , Lamps , L. W. , Nanney , L. B. , Beauchamp , R. D. and Dubois , R. N.Elevated cyclooxygenase‐2 levels in Min mouse adenomas . Gastroenterology , 110 , 1259 – 1262 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Morris , P. and Phyllis , H. L.Prevention and treatment of primary intestinal tumor in rats by piroxicam . Cancer Res. , 49 , 6471 – 6473 ( 1989. ). [PubMed] [Google Scholar]
  • 31. ) Su , L. K. , Kinzler , K. W. , Volgenstein , B. , Preisinger , A. C. , Mosser , A. R. , Luongo , C. , Gould , K. A. and Dove , W. F.Multiple intestinal neoplasia caused by a mutation in the murine homologue of the APC gene . Science , 256 , 668 – 670 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Prosad , K. N.Butyric acid, a small fatty acid with diverse biological functions . Life Sci. , 27 , 1351 – 1358 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Van Munster , I. P. and Nagengast , F. M.The role of carbohydrate fermentation in colon cancer prevention . Scand. J. Gastroenterol. , 200 , 80 – 86 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Lupton , J. and Kurtz , P.Relationship of colonic luminal short‐chain fatty acids and pH to in vivo cell proliferation in rats . J. Nutr. , 123 , 1522 – 1530 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Sakata , T.Stimulatory effect of short‐chain fatty acids on epithelial cells of the rat colon . Gastroenterology , 83 , 425 – 429 ( 1987. ). [Google Scholar]
  • 36. ) Bradburn , D. M. , Mathers , J. C. , Gunn , A. , Burn , J. , Chapman P. D. , and Johnston , I. D. A.Colonic fermentation of complex carbohydrates in patients with familial adenomatous polyposis . Gut , 34 , 630 – 636 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

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