Advertisement

Specific COX-2 inhibitors: from bench to bedside

  • P. Isakson
  • B. Zweifel
  • J. Masferrer
  • C. Koboldt
  • K. Seibert
  • R. Hubbard
  • S. Geis
  • P. Needleman

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been used to treat various ailments for over 100 years. As a class, these drugs are anti-inflammatory, analgesic and anti-pyretic, and they are widely used to treat chronic inflammatory diseases such as arthritis. The commercially available NSAIDs are approximately equivalent in terms of anti-inflammatory efficacy. All of the NSAIDs, however, also cause adverse effects in a significant fraction of people who consume them, and these side-effects frequently limit therapy. The most common side-effects associated with NSAID therapy are gastrointestinal (GI), with haemorrhage and frank ulceration seen in some patients; these lesions apparently can lead to increased morbidity in long-term NSAID users1. Renal and CNS effects are also observed. Because of these problems, a major goal of the pharmaceutical industry is the development of drugs that possess anti-inflammatory activity but lack the toxic effects associated with current NSAIDs. To date, no NSAIDs with the desired therapeutic profile have been commercially developed.

Keywords

Inducible Cyclooxygenase Current NSAID Sheep Vesicular Gland Seminal Vesicle Sheep 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell R. Gastrointestinal damage associated with the use of non-steroidal anti-inflammatory drugs. New England J Med. 1992; 327: 749–754.CrossRefGoogle Scholar
  2. 2.
    Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirinlike drugs. Nature New Biol. 1971; 231: 232–235.PubMedGoogle Scholar
  3. 3.
    Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin formation in human platelets. Nature New Biol. 1971; 231: 235–239.PubMedGoogle Scholar
  4. 4.
    Vane JR, Botting RM. Biological properties of cyclooxygenase products. In: Cunningham FM (ed.) Lipid Mediators. London: Academic Press Ltd, 1994; 61–97.Google Scholar
  5. 5.
    Portanova J, Zhang Y, Anderson GD et al. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia and IL-6 production in vivo. J Exp Med. 1996; 184: 883–891.PubMedCrossRefGoogle Scholar
  6. 6.
    Morrison AR, Nishikawa KA, Needleman P. Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney. Nature. 1977; 267: 259–260.PubMedCrossRefGoogle Scholar
  7. 7.
    Needleman P, Wyche A, Bronson SD, Holmberg S, Morrison AR. J Biol Chem. 1979; 254: 9772–9777.PubMedGoogle Scholar
  8. 8.
    Raz A, Wyche A, Siegel N, Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl Acad Sci USA. 1989; 86: 1657–1661.PubMedCrossRefGoogle Scholar
  9. 9.
    Masferrer JL, Seibert K, Zweifel BS, Needleman P. Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc Natl Acad Sci USA. 1992; 89: 3917–3921.PubMedCrossRefGoogle Scholar
  10. 10.
    Masferrer JL, Zweifel BS, Seibert K, Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest. 1990; 86: 1375–1379.PubMedCrossRefGoogle Scholar
  11. 11.
    Merlie JP, Fagan D, Mudd J, Needleman P. Isolation and characterization of complementary DNA for sheep seminal vesicle sheep prostaglandin endoperoxide synthase. J Biol Chem. 1988; 263: 3550–3553.PubMedGoogle Scholar
  12. 12.
    DeWitt D, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci USA. 1988; 85: 1412–1416.PubMedCrossRefGoogle Scholar
  13. 13.
    Yokoyama C, Takai T, Tanabe T. Primary structure of sheep prostaglandin endoperoxide synthase deduced from cDNA sequence. FEBS Lett. 1988; 231: 347–351.PubMedCrossRefGoogle Scholar
  14. 14.
    Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA. 1991; 88: 2692–2696.PubMedCrossRefGoogle Scholar
  15. 15.
    Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991; 266: 12866–12872.PubMedGoogle Scholar
  16. 16.
    O’Banion MK, Sadowski HB, Winn V, Young DA. A serum-and glucocorticoid regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem. 1991; 266: 23261–23267.PubMedGoogle Scholar
  17. 17.
    Fletcher BS, Kujubu DA, Perrin DM, Herschman HR. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem. 1992; 267: 4338–4344.PubMedGoogle Scholar
  18. 18.
    Sirois J, Richards JS. Purification and characterization of a novel, distinct isoform of prostaglandin endoperoxide synthase induced by human chorionic gonadotropin in granulosa cells of rat preovulatory follicles. J Biol Chem. 1992; 267: 6382–6388.PubMedGoogle Scholar
  19. 19.
    Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem. 1992; 267: 7991–7994.PubMedGoogle Scholar
  20. 20.
    O’Banion MK, Winn V, Young DA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA. 1992; 89: 4888–4892.PubMedCrossRefGoogle Scholar
  21. 21.
    Kujubu DA, Reddy ST, Fletcher BS, Herschman H. Expression of the protein product of the prostaglandin synthase-2/TIS10 gene in mitogen-stimulated Swiss 3T3 cells. J Biol Chem. 1993; 268: 5425–5430.PubMedGoogle Scholar
  22. 22.
    Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 1994; 367: 243–249.PubMedCrossRefGoogle Scholar
  23. 23.
    Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384: 644–648.PubMedCrossRefGoogle Scholar
  24. 24.
    Gierse J, McDonald J, Hauser S, Rangwala S, Seibert K. A single amino acid difference between cyclooxygenase-1 (COX-1) and-2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem. 1996; 271: 15810–15814.PubMedCrossRefGoogle Scholar
  25. 25.
    Futaki N, Arai I, Hamasaki S, Takahashi S, Higuchi S, Otomo S. Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation. J Pharm Pharmacol. 1992; 45: 753–755.CrossRefGoogle Scholar
  26. 26.
    Futaki N, Yoshikawa K, Yumiko H et al. NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effect, which causes minimal stomach lesions. Gen Pharmacol. 1993; 24: 105–110.PubMedCrossRefGoogle Scholar
  27. 27.
    Gans KR, Galbraith W, Roman RJ et al. Anti-inflammatory and safety profile of DuP 697; a novel orally effective prostaglandin synthesis inhibitor. J Pharmacol Exp Ther. 1989; 254: 180–187.Google Scholar
  28. 28.
    Masferrer J, Zweifel B, Manning PT et al. Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and non-ulcerogenic. Proc Natl Acad Sci USA. 1994; 91: 3228–3232.PubMedCrossRefGoogle Scholar
  29. 29.
    Seibert K, Zhang Y, Leahy K et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. 1994; 91: 12013–12017.PubMedCrossRefGoogle Scholar
  30. 30.
    Chan C, Boyce S, Brideau C et al. Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: A novel non-steroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach. J Pharm Exp Ther. 1995; 274: 1531–1537.Google Scholar
  31. 31.
    Penning TD, Talley JJ, Bertenshaw SR et al. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of SC-58635 (celecoxib). J Med Chem. 1997; 40: 1347–1365.PubMedCrossRefGoogle Scholar
  32. 32.
    Rome LH, Lands WEM. Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc Natl Acad Sci USA. 1975; 72: 4863–4865.PubMedCrossRefGoogle Scholar
  33. 33.
    Copeland RA, Williams JM, Giannaras J et al. Mechanisms of selective inhibition of the inducible isoform of prostaglandin G/H synthase. Proc Natl Acad Sci USA. 1994; 91: 11202–11206.PubMedCrossRefGoogle Scholar
  34. 34.
    Gierse JK, Hauser SD, Creely DP et al. Expression and selective inhibition of the constitutive and inducible forms of human cyclooxygenase. Biochem J. 1995; 305: 479–484.PubMedGoogle Scholar
  35. 35.
    Frölich JC. A classification of NSAIDs according to the relative inhibition of cyclooxygenase isoenzymes. Trends Pharm Sci. 1997; 18: 30–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Kargman S, Charleson S, Cartwright M et al. Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology. 1996; 111:445–454.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • P. Isakson
  • B. Zweifel
  • J. Masferrer
  • C. Koboldt
  • K. Seibert
  • R. Hubbard
  • S. Geis
  • P. Needleman

There are no affiliations available

Personalised recommendations