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Cyclooxygenase-1 and Cyclooxygenase-2 Knockout Mice Provide Insights into Beneficial and Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs

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Book cover COX-2 Blockade in Cancer Prevention and Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Two isoforms of cyclooxygenase (COX-1 and COX-2) are known and both catalyze the first committed step in the pathway leading to the production of prostaglandins (PGs), i.e., PGE2, PGD2, PGI2, PGF2, and thromboxane A2 (1) Both isoforms are biological targets for the widely used class of medicines known as nonsteroidal anti-inflammatory drugs (NSAIDs); and NSAIDs are believed to cause their biological effects by effectively reducing PG production. However, because studies indicated that COX-1 and COX-2 have different physiological functions (2), NSAIDs with increased isoform selectivity have been developed. As COX-1 was the isoform believed to generate PGs associated with house keeping functions, and COX-2 was the isoform believed to produce PGs associated with the development of several diseases, the emphasis has been to develop NSAIDs with increased selectivity for COX-2.

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References

  1. Smith WL, DeWitt DL. Prostaglandin endoperoxide H synthases-1 and-2. Adv Immunol 1996; 62: 167215.

    Google Scholar 

  2. Smith W, Langenbach R. Why there are two cyclooxygenase isozymes. J Clin Invest 2001; 107: 1591 1595.

    Google Scholar 

  3. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacininduced gastric ulceration. Cell 1995; 83: 483–492.

    Article  PubMed  CAS  Google Scholar 

  4. Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995; 83: 473–482.

    Article  PubMed  CAS  Google Scholar 

  5. Gross GA, Imamura T, Luedke C, Vogt SK, Olson LM, Nelson DM, et al. Opposing actions of Prostaglandins and oxytocin determine the onset of murine labor. Proc Natl Acad Sci USA 1998; 95:11, 87511, 879.

    Google Scholar 

  6. Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997; 91: 197–208.

    Article  PubMed  CAS  Google Scholar 

  7. Dinchuk, JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995; 378: 406–409.

    Article  PubMed  CAS  Google Scholar 

  8. Loftin CD, Tiano HF, Trivedi DB, Clark JA, Lee CA, Epstein JA, et al. Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and -2. Proc Nall Acad Sci USA 2001; 98: 1059–1064.

    Article  CAS  Google Scholar 

  9. Komhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, et al. Cyclooxygenase-2selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int 2000; 57: 414422.

    Google Scholar 

  10. Davis, BJ, Lennard DE, Lee CA, Tiano HF, Morham SG, Wetsel WC, et al. Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E2 and interleukin-1 beta. Endocrinology 1999; 140: 2685–2695.

    Article  PubMed  CAS  Google Scholar 

  11. Langenbach R, Loftin C, Lee C, Tiano H. Cyclooxygenase knockout mice models for elucidating isoform-specific functions. Biochem Pharmacol 1999; 58: 1237–1246.

    Article  PubMed  CAS  Google Scholar 

  12. Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000; 119: 706–714.

    Article  PubMed  CAS  Google Scholar 

  13. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul Clark MJ, Willoughby DA. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 1999; 5: 698–701.

    Article  PubMed  CAS  Google Scholar 

  14. Shoemaker AR, Gould KA, Luongo C, Moser AR, Dove WF. Studies of neoplasia in the Min mouse. Biochim Biophys Acta 1997; 1332: F25 - F48.

    PubMed  CAS  Google Scholar 

  15. Tiano HF, Chulada PC, Spalding J, Lee CA, Loftin CD, Mahler JF, et al. Effects of cyclooxygenase deficiency on inflammation and papilloma formation in mouse skin. Proc Am Assoc Cancer Res 1998; 38: 257 (Abstract).

    Google Scholar 

  16. Chulada PC, Thompson MB, Mahler JF, Doyle CM, Gaul BW, Lee C, et al. Genetic disruption of Ptgs1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 2000; 60: 4705–4708.

    PubMed  CAS  Google Scholar 

  17. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al. Suppression of intestinal polyposis in Apc(Delta 716) knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87: 803–809.

    Article  PubMed  CAS  Google Scholar 

  18. Fischer SM, Lo HH, Gordon GB, Seibert K, Kelloff G, Lubet RA, et al. Chemopreventive activity of Celecoxib, a specific cyclooxygenase-2 inhibitor and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog 1999; 25: 231–240.

    Article  PubMed  CAS  Google Scholar 

  19. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995; 83: 493–501.

    Article  PubMed  CAS  Google Scholar 

  20. Tsujii M, Kawano S, Tsuji S, Sawaka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705–712.

    Article  PubMed  CAS  Google Scholar 

  21. Tiano H, Loftin C, Lee C, et al. Deficiency of cyclooxygenase-1 or cyclooxygenase-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res (in press).

    Google Scholar 

  22. Zhang X, Morham SG, Langenbach R, Young DA. Malignant transformation and anti-neoplastic actions of NSAIDS on cyclooxygenase-null embryo fibroblasts. J Exp Med 1999; 190: 451–459.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang X, Morham SG, Langenbach R, Baggs RB, Young DA. Lack of cyclooxygenase-2 inhibits growth of teratocarcinomas in mice. Exp Cell Res 2000; 254: 232–240.

    Article  PubMed  CAS  Google Scholar 

  24. Reddy ST, Tiano HF, Langenbach R, Morham SG, Herschman HR. Genetic differences for distinct roles of COX-1 and COX-2 in the intermediate and delayed phases of prostaglandin synthesis in mast cells. Biochem Biophys Res Commun 1999; 265: 205–210.

    Article  PubMed  CAS  Google Scholar 

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Langenbach, R. (2003). Cyclooxygenase-1 and Cyclooxygenase-2 Knockout Mice Provide Insights into Beneficial and Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs. In: Harris, R.E. (eds) COX-2 Blockade in Cancer Prevention and Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-302-6_9

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  • DOI: https://doi.org/10.1007/978-1-59259-302-6_9

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-304-6

  • Online ISBN: 978-1-59259-302-6

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