Matrix Metalloproteinase Inhibitors

  • Peter D. Brown
  • Mark Whittaker
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Matrix metalloproteinases(MMPs) are a family of structurally related realted enzymes that are capable of degrading of the extracellular matrix. One of the earliest descriptions of MMPs was as depolymerizing enzymes, including that of small blood vessels,morefluid (1).Sudequent research has shown that these enzymes paly a central role in the tissue remodeling associated with both physiological and pathogenic processes.


Experimental Autoimmune Encephalomyelitis Hydroxamic Acid Betulinic Acid Human Amniotic Membrane Matrix Metalloproteinase Inhibitor 
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.


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  1. 1.
    Gersh, I. and Catchpole, H. R. (1949) Organization of ground substance and basement membrane and its significance in tissue injury, disease and growth. Am. J. Anat. 85, 457–507.PubMedCrossRefGoogle Scholar
  2. 2.
    Wilhelm, S. C., Eisen, A. Z., Teter, M., Clark, S. D., Kronberger, A., and Goldberg, G. (1986) Human fibroblast collagenase: glycosylation and tissue-specifiic levels of enzyme synthesis. Proc. Natl. Acad. Sci. USA 83, 3756–3760.PubMedCrossRefGoogle Scholar
  3. 3.
    Hasty, K. A., Pourmotabbed, T. F., Goldberg, G. I., Thompson, J. P., Spinella, D. G., Stevens, R. M., and Mainardi, C. L. (1990) Human neutrophil collagenase; a distinct gene product with homology to other matrix metalloproteinases. J. Biol. Chem. 265, 11,421–11,424.Google Scholar
  4. 4.
    Collier, I. E., Wilhelm, S. M., Eisen, A. Z., Marmer, B. L., Grant, G. A., Seltzer, J. L., et al. (1988) H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J. Biol. Chem. 263, 6579–6587.PubMedGoogle Scholar
  5. 5.
    Wilhelm, S. M., Collier, I. E., Marmer, B. L., Eisen, A. Z., Grant, G. A., and Goldberg, G. I. (1989) SV40–transformed human lung fibroblasts secrete a 92–kDa Type IV collagenase which is identical to that secreted by normal human macrophages. J. Biol. Chem. 264, 17,213–17,221.Google Scholar
  6. 6.
    Liotta, L. A., Tryggvason, K., Garbisa, S., Robey, P. G., and Abe, S. (1981) Partial purification and characterisation of a neutral protease which cleaves type IV collagen. Biochemistry 20, 100–104.PubMedCrossRefGoogle Scholar
  7. 7.
    Senior, R. M., Griffin, G. L., Fliszar, C. J., Shapiro, S. D., Goldberg, G. I., and Welgus, H. G. (1991) Human 92- and 72-kilodalton type IV collagenases are elastases. J. Biol. Chem. 266, 7870–7875.PubMedGoogle Scholar
  8. 8.
    Wilhelm, S. M., Collier, I. E., Kronberger, A., Eisen, A. Z., Marmer, B. L., Grant, G. G., Bauer, E. A., and Goldberg, G. I. (1987) Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumourigenic cells. Proc. Natl. Acad. Sci. USA 84, 6725–6729.PubMedCrossRefGoogle Scholar
  9. 9.
    Muller, D., Quantin, B., Gesnel, M. C., Millon-Collard, R., Abecassis, J., and Breathnach, R. (1988) The collagenase gene family in humans consists of at least four members. Biochem. J. 253,187–192.Google Scholar
  10. 10.
    Basset, P., Bellocq, J. P., Wolf, C., Stoll, I., Hutin, P., Limacher, J. M., et al. (1990) A novel metalloproteinase gene specifically expressed in stromal cell of breast carcinomas. Nature 348, 699–704.PubMedCrossRefGoogle Scholar
  11. 11.
    Pei, D., Majmudar, G., and Weiss, S. J. (1994) Hydrolytic inactivation of a breast carcinoma cellderived serpin by human stromelysin-3. J. Biol. Chem. 269, 25,849–25,855.Google Scholar
  12. 12.
    Quantin, B., Murphy, G., and Breathnach, R. (1989) Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochemistry 28, 5325–5334.CrossRefGoogle Scholar
  13. 13.
    Shapiro, S. D., Kobayashi, D. K., and Ley, T. J. (1993) Cloning and characterisation ofa unique elastolytic metalloproteinase produced by human alveolar macrophages. J. Biol. Chem. 268, 23,824–23,829.Google Scholar
  14. 14.
    Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370, 61–65.Google Scholar
  15. 15.
    Will, H. and Hinzmann, B. (1995) cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment. Eur. J. Biochem. 231, 602–608.Google Scholar
  16. 16.
    Takino, T., Sato, H., Shinagawa, A., and Seiki, M. (1995) Identification of the second membrane-type matrix metalloproteinase (MT-MMP2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family. J. Biol. Chem. 270, 23,013–23,020.Google Scholar
  17. 17.
    Puente, X. S., Pendas, A. M., Llano, E., Velasco, G., and Lopez-Otin, C. (1996) Molecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma. Cancer Res. 56, 944–949.PubMedGoogle Scholar
  18. 18.
    Strongin, A., Collier, I., Bannikov, G., Marmer, B. L., Grant, G. A., and Goldberg G. I. (1995) Mechanism of cell surface activation of 72kDa type IV collagenase. J. Biol. Chem. 270, 5331–5338.Google Scholar
  19. 19.
    Ohuchi, E., Imai, K., Sato, H., Seiki, M., and Okada, Y. (1997) Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 272, 2446–2451.PubMedCrossRefGoogle Scholar
  20. 20.
    Cossins, J., Dudgeon, T. J., Catlin, G., Gearing, A. J. H., and Clements, J. M. (1996) Identifiication of MMP-18, a putative novel human matrix metalloproteinase. Biochem. Biophys. Res. Commun. 228, 494–498.PubMedCrossRefGoogle Scholar
  21. 21.
    Gearing, A. J. H., Beckett, P., Christodoulou, M., Churchill, M., Clements, J., Davidson A. H., et al. (1994) Processing oftumour necrosis factor-a precursor by metalloproteinases. Nature 370, 555–557.PubMedCrossRefGoogle Scholar
  22. 22.
    Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J., and Slack, J. L. (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729–733.PubMedCrossRefGoogle Scholar
  23. 23.
    Moss, M. L., Jin, S. L., Milla, M. E., Burkhart, W., and Carter, H. L. (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385, 733–736.PubMedCrossRefGoogle Scholar
  24. 24.
    Docherty, A. J. P., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., and Harris, T. J. R. (1985) Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318, 66–69.PubMedCrossRefGoogle Scholar
  25. 25.
    Stetler-Stevenson, W. G., Krutzsch, H. C., and Liotta, L. A. (1989) Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. J. Biol. Chem. 264, 17,374–17,378.Google Scholar
  26. 26.
    Apte, S. S., Mattei, M. G., and Olsen, B. R. (1994) Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and the mapping of the TIMP-3 gene to chromosome 22. Genomics 19, 86–90.PubMedCrossRefGoogle Scholar
  27. 27.
    Greene, J., Wang, M. S., Liu, Y. L. E., Raymond, L. A., Rosen, C., and Shi, Y. N. E. (1996) Molecular cloning and characterisation of human tissue inhibitor of metalloproteinase 4. J. Biol. Chem. 271, 30,375–30,380.Google Scholar
  28. 28.
    Butler, T. A., Zhu, C., Mueller, R. A., Fuller, G. C., Lemaire, W. J., and Woessner, J. F. (1991) Inhibition of ovulation in the perfused rat ovary by synthetic collagenase inhibitor SC44463. Biol. Reprod. 44, 1183–1188.PubMedCrossRefGoogle Scholar
  29. 29.
    Graham, C. H. and Lala, P. K. (1991) Mechanism of control of trophoblast invasion in situ. J. Cell. Physiol. 148, 228–234.Google Scholar
  30. 30.
    Gack, S., Vallon, R., Schmidt, J., Grigoriadis, A., Tuckermann, J., Schenkel, J., et al. (1995) Expression of interstitial collagenase during skeletal development of the mouse is restricted to osteoblast-like cells and hypertrophic chondrocytes. Cell Growth Diffff. 6, 759–767.Google Scholar
  31. 31.
    Karelina, T. V., Goldberg, G. I., and Eisen, A. Z. (1994) Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J. Invest. Derm. 103, 482–487.PubMedCrossRefGoogle Scholar
  32. 32.
    Lund, L. R., Romer, J., Thomasset, N., Solberg, H., Pyke, C., Bissell, M. J., Dano, K., and Werb, Z. (1996) Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development 122, 181–193.Google Scholar
  33. 33.
    Cawston, T. E. (1996) Metalloproteinase inhibitors and the prevention of tissue breakdown. Pharm. Ther. 70, 163–182.CrossRefGoogle Scholar
  34. 34.
    O’Byrne, E. M., Parker, D. T., Roberts, E. D., Goldberg, R. L., MacPherson, L. J., Blancuzzi, V., et al. (1995) Oral administration of a matrix metalloproteinase inhibitor, CGS 27023A, protects the cartilage proteoglycan matrix in a partial meniscectomy model of osteoarthritis in rabbits. Inflam. Res. 44, S 117, 118.Google Scholar
  35. 35.
    Liotta, L. A. and Stetler-Stevenson, W. G. (1990) Metalloproteinases and cancer invasion. Semin. Cancer Biol. 1, 99–106.PubMedGoogle Scholar
  36. 36.
    Gijbels, K., Masure, S., Carton, H., and Opdenakker, G. (1992) Gelatinase in cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J. Neuroimmunol. 41, 29–34.PubMedCrossRefGoogle Scholar
  37. 37.
    Chandler, S., Coates, R., Gearing, A., Lury, J., Wells, G., and Bone, E. (1995) Matrix metalloproteinases degrade myelin basic protein. Neurosci. Lett. 201, 223–226.PubMedCrossRefGoogle Scholar
  38. 38.
    Rosenberg, G. A. (1995) Matrix metalloproteinases in brain injury. J. Neurotrauma 12, 833–842.PubMedCrossRefGoogle Scholar
  39. 39.
    Strauss, B. H., Robinson, R., Batchelor, W. B., Chisholm, R. J., Natarajan, M. K., Logan, R. A., et al. (1996) In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases. Circ. Res. 79, 541–550.PubMedCrossRefGoogle Scholar
  40. 40.
    Thompson, R. W. and Parks, W. C. (1996) Role of matrix metalloproteinases in abdominal aortic aneurysms. Ann. NY Acad. Sci. 800, 157–174.PubMedCrossRefGoogle Scholar
  41. 41.
    Saarialho-Kere, U. K., Vaalamo, M., Puolakkainen, P., Airola, K., Parks, W. C., and KarjalainenLindsberg, M. L. (1996) Enhanced expression of matrilysin, collagenase and stromelysin-1 in gastrointestinal ulcers. Am. J. Pathol. 148, 519–526.PubMedGoogle Scholar
  42. 42.
    Morphy, J. R., Millican T. A., and Porter J. R. (1995) Matrix metalloproteinase inhibitors: current status. Curr. Med. Chem. 2, 743–762.Google Scholar
  43. 43.
    Beckett, R. P., Davidson, A. H., Drummond, A. H., Huxley, P., and Whittaker, M. (1996) Recent advances in matrix metalloproteinase inhibitor research. Drug Discovery Today 1, 16–26.CrossRefGoogle Scholar
  44. 44.
    Zask, A., Levin, J. I., Killar, L. M., and Skotnicki, J. S. (1996) Inhibition of matrix metalloproteinases: structure based design. Curr. Pharm. Des. 2, 624–661.Google Scholar
  45. 45.
    Hagmann, W. K., Lark, M. W., and Becker, J. W. (1996) Inhibition of matrix metalloproteinases. Ann. Rep. Med. Chem. 31, 231–240.CrossRefGoogle Scholar
  46. 46.
    Davidson, A. H., Drummond A. H., Galloway, W. A., and Whittaker, M. (1997) Inhibition of matrix metalloproteinase enzymes. Chem. Ind. 7, 258–261.Google Scholar
  47. 47.
    White, A. D., Bocan, T. M. A., Boxer, P. A., Peterson, J. T., and Schrier, D. (1997) Emerging therapeutic advances for the development of second generation matrix metalloproteinase inhibitors. Curr. Pharm. Des. 3, 45–58.Google Scholar
  48. 48.
    Schwartz, M. A. and Van Wart, H. E. (1992) Synthetic inhibitors of bacterial and mammalian interstitial collagenases. Prog. Med. Chem. 29, 271–334.PubMedCrossRefGoogle Scholar
  49. 49.
    Netzel-Arnett, S., Sang, Q. X., Moore, W. G. I., Navre, M., Birkedal-Hansen, H., and Van Wart, H. E. (1993) Comparative sequence specificities of human 72- and 92-kDa gelatinases (type IV collagenases) and PUMP (matrilysin). Biochemistry 32, 6427–6432.PubMedCrossRefGoogle Scholar
  50. 50.
    McGeehan, G. M., Bickett, D. M., Green, M., Kassel, D., Wiseman, J. S., and Berman, J. (1994) Characterisation of the peptide substrate specificities of interstitial collagenase and 92-kDa gelatinase. J. Biol. Chem. 269, 32,814–32,820.Google Scholar
  51. 51.
    Smith, M. M., Shi, L. H., and Navre, M. (1995) Rapid identifiication of highly active and selective substrates for stromelysin and matrilysin using bacteriophage peptide display libraries. J. Biol. Chem. 270, 6440–6449.PubMedCrossRefGoogle Scholar
  52. 52.
    Lovejoy, B., Cleasby, A., Hassell, A. M., Longley, K., Luther, M. A., Weigl, D., et al. (1994) Structure of the catalytic domain of fibroblast collagenase complexed with an inhibitor. Science 263, 375–377.PubMedCrossRefGoogle Scholar
  53. 53.
    Borkakoti, N., Winkler, F. K., Williams, D. H., D’Arcy, A., Broadhurst, M. J., Brown, P. A., Johnson, W. H., and Murray, E. J. (1994) Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitor. Struct. Biol. 1, 106–110.CrossRefGoogle Scholar
  54. 54.
    Stams, T., Spurlino, J. C., Smith, D. L., Wahl, R. C., Ho, T. F., Qoronfleh, M. W., Banks, T. M., and Rubin, B. (1994) Structure ofhuman neutrophil collagenase reveals large S 1’ specificity pocket. Struct. Biol. 1, 119–123.CrossRefGoogle Scholar
  55. 55.
    Bode, W., Reinemer, P., Huber, R., Kleine, T., Schnierer, S., and Tschesche, H. (1994) X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specifiicity, EMBO J. 13, 1263–1269.PubMedGoogle Scholar
  56. 56.
    Spurlino, J. C., Smallwood, A. M., Carlton, D. D., Banks, T. M., Vavra, K. J., Johnson, J. S., et al. (1994) 1.560A Structure of mature truncated human fibroblast collagenase, Proteins: Structure, Function, Genet. 19, 98–109.Google Scholar
  57. 57.
    Grams, F., Reinemer, P., Powers, J. C., Kleine, T., Pieper, M., Tschesche, H., Huber, R., and Bode, W. (1995) X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors: implications for substrate binding and rational drug design. Eur. J. Biochem. 228, 830–841.PubMedCrossRefGoogle Scholar
  58. 58.
    Browner, M. F., Smith, W. W., and Castelhano, A. L. (1995) Matrilysin-inhibitor complexes: Common themes among metalloproteinases, Biochemistry 34, 6602–6610.PubMedCrossRefGoogle Scholar
  59. 59.
    Grams, F., Crimmin, M., Hinnes, L., Huxley, P., Pieper, M., Tscheshe, H., and Bode, W. (1995) Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. Biochemistry 34, 14,012–14,020.Google Scholar
  60. 60.
    Becker, J. W., Marcy, A. I., Rokosz, L. L., Axel, M. G., Burbaum, J. J., Fitzgerald, P. M. D., et al. (1995) Stromelysin-I: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Protein Sci. 4, 1966–1976.PubMedCrossRefGoogle Scholar
  61. 61.
    Dhanaraj, V., Ye, Q-Z., Johnson, L. L., Hupe, D. J., Ortwine, D. F., Dunbar, J. B., et al. (1996) X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily. Curr. Biol. 4, 375–386.Google Scholar
  62. 62.
    Babine, R. E. and Bender, S. L. (1997) Molecular recognition of protein-ligand complexes: applications to drug design. Chem. Rev. 97, 1359–1472.PubMedCrossRefGoogle Scholar
  63. 63.
    Gooley, P. R., O’Connell, J. F., Marcy, A. I., Cuca, G. C., Axel, M. G., Caldwell, C. G., Hagmann, W. K., and Becker, J. W. (1996) Comparison of the structure of human recombinant short form stromelysin by multidimensional heteronuclear NMR and x-ray crystallography. J. Biomol. NMR 7, 8–28.PubMedCrossRefGoogle Scholar
  64. 64.
    Campbell, D. A., Bermak, J. C., Burkoth, T. S., and Patel, D. V. (1995) Transition state analogue inhibitor combinatorial library. J. Am. Chem. Soc. 117, 5381, 5382.Google Scholar
  65. 65.
    Foley, M. A., Hassman, A. S., Drewry, D. H., Greer, D. G., Wagner, C. D., Feldman, P. L., et al. (1996) Rapid synthesis of novel dipeptide inhibitors of human collagenase and gelatinase using solid phase chemistry. Bioorg. Med. Chem. Lett. 16, 905–1910.Google Scholar
  66. 66.
    Rockwell, A., Melden, M., Copeland, R. A., Hardman, K., Decicco, C. P., and DeGrado, W. F. (1996) Complementarity of combinatorial chemistry and structure-based ligand design: application of the discovery of novel inhibitors of matrix metalloproteinases. J. Am. Chem. Soc. 118, 10,337–10,338.Google Scholar
  67. 67.
    Schullek, J. R., Butler, J. H., Ni, Z-J., Chen, D., and Yuan, Z. (1997) A high-density screening format for encoded combinatorial libraries: assay miniaturization and its application to enzymatic reactions. Anal. Biochem. 246, 20–29.PubMedCrossRefGoogle Scholar
  68. 68.
    Galardy, R. E. (1993) Galardin. Drugs Future 18, 1109–1111.Google Scholar
  69. 69.
    Brown, P. D. and Giavazzi, R. (1995) Matrix metalloproteinase inhibition: a review of anti-tumour activity. Ann. Oncol. 6, 967–974.PubMedGoogle Scholar
  70. 70.
    Ngo, J., Graul, A., and Castaner, J. (1996) Batimastat. Drugs Future 21, 1215–1220.Google Scholar
  71. 71.
    Lelievre, Y., Bouboutou, R., Boiziau, J., and Cartwright, T. (1989) Inhibition de la collagenase synoviale par 1’actinonine etude de relations structure/activite. Pathol. Biol. 37, 43–46.PubMedGoogle Scholar
  72. 72.
    Naito, K., Nakajima, S., Kanbayashi, N., Okuyama, A., and Goto, M. (1993) Inhibition of metalloproteinase activity of rheumatoid arthritis synovial cells by a new inhibitor [BE16627B; L-N-(N-hydroxy-2-isobutylsuccinamoyl)-seryl-L-valine]. Agents Actions 39, 182–186.PubMedCrossRefGoogle Scholar
  73. 73.
    Tamaki, K., Kurihara, S., Oikawa, T., Tanzawa, K., and Sugimura, Y. (1994) Matlystatins, new inhibitors of type IV collagenases from Actinomadura atramentaria: IV. Synthesis and structureactivity relationships of matlystatin B and its stereoisomers, J. Antibiot. 47, 1481–1492.PubMedCrossRefGoogle Scholar
  74. 74.
    Sato, T., Takebayashi, Y., Tokunaga, T., and Ozasa, T. (1996) YM-24074, a new peptide antibiotic II. Structural elucidation. J. Antibiot. 49, 811–815.PubMedCrossRefGoogle Scholar
  75. 75.
    Porter, J. R., Beeley, N. R. A., Boyce, B. A., Mason, B., Millican, A., Millar, K., et al. (1994) Potent and selective inhibitors of gelatinase-A I. Hydroxamic acid derivatives. Bioorg. Med. Chem. Lett. 4, 2741–2746.Google Scholar
  76. 76.
    Singh, J., Conzentino, P., Cundy, K., Gainor, J. A., Gilliam, C. L., Gordon, T. D., et al. (1995) Relationship between structure and bioavailability in a series ofhydroxamate based metalloproteinase inhibitors. Bioorg. Med. Chem. Lett. 5, 337–342.CrossRefGoogle Scholar
  77. 77.
    Chander, S. K., Antoniw, P., Beeley, N. R. A., Boyce, B., Crabbe, T., Docherty, A. J. P., et al. (1995) An in vivo model for screening peptidomimetic inhibitors of gelatinase A. J. Pharm. Sci. 84,404–409.Google Scholar
  78. 78.
    Hirayama, R., Yamamoto, M., Tsukida, T., Matsuo, K., Obata, Y., Sakamoto, F., and Ikeda, S. (1997) Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. Bioorg. Med. Chem. 5, 765–778.PubMedCrossRefGoogle Scholar
  79. 79.
    MacPherson, L. J., Bayburt, E. K., Capparelli, M. P., Carroll, B. J., Goldstein, R., Justice, M. R., et al. (1997) Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J. Med. Chem. 40, 2525–2532.PubMedCrossRefGoogle Scholar
  80. 80.
    Bender, S. L. (1997) Structure-based design of MMP inhibitors: Discovery and development of AG3340. SRI Conference; Rational drug discovery via combinatorial chemistry and structure-based design, Princeton, NJ, September 15–16.Google Scholar
  81. 81.
    Johnson, W. H., Roberts, N. A., and Borkakoti, N. (1987) collagenase inhibitors: their design and potential therapeutic use. J. Enz. Inhib. 2, 1–22.Google Scholar
  82. 82.
    Bottomley, K. M., Borkakoti, N., Bradshaw, D., Brown, P. A., Broadhurst M. J., Budd, J. M., et al. (1997) Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors. Biochem. J. 323, 483–488.PubMedGoogle Scholar
  83. 83.
    Broadhurst, M. J., Brown, P. A., Lawton, G., Ballantyne, N., Borkakoti, N., Bottomley, K. M. K., et al. (1997) Design and synthesis of the cartilage protective agent (CPA, Ro 32–3555). Bioorg. Med. Chem. Lett. 7, 2299–2302.CrossRefGoogle Scholar
  84. 84.
    Lewis, E. J., Bishop, J., Bottomley,K. M. K., Bradshaw, D., Brewster, M., Broadhurst, M. J., et al. (1997) Ro 32–3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo. Br. J. Pharmacol. 121, 540–546.PubMedCrossRefGoogle Scholar
  85. 85.
    Beckett, R. P. (1996) Recent advances in the field of matrix metalloproteinase inhibitors. Exp. Opin. Ther. Patents 6, 1305–1315.CrossRefGoogle Scholar
  86. 86.
    Castelhano, A. L., Billedeau, R., Dewdney, N., Donnelly, S., Horne, S., Kurz, L. J., et al. (1995) Novel indolactambased inhibitors of matrix metalloproteinases. Bioorg. Med. Chem. Lett. 5, 1415–1420.CrossRefGoogle Scholar
  87. 87.
    Esser, K. E., Bugianesi, R. L., Caldwell, C. G., Chapman, K. T., Durette, P. L., Girotra, N. N., et al. (1997) Inhibition of stromelysin-1 (MMP-3) by P1’-biphenylylethyl carboxyalkyl dipeptides. J. Med. Chem. 40, 1026–1040.Google Scholar
  88. 88.
    Baxter, A. D., Bird, J., Bhogal, R., Massil, T., Minton, K. J., Montana, J., and Owen, D. A. (1997) A novel series ofmatrix metalloproteinase inhibitors for the treatment of inflammatory disorders. Bioorg. Med. Chem. Lett. 7, 897–902.CrossRefGoogle Scholar
  89. 89.
    Harris, G. H., Hoogsteen, K., Silverman, K. C., Raghoobar, S. L., Bills, G. F., Lingham, R. B., et al. (1993) Isolation and structure determination of pycnidione, a novel bistropolone stromelysin inhibitor from a Phoma sp. Tetrahedron 49, 2139–2144.CrossRefGoogle Scholar
  90. 90.
    Yeh, L-A., Chen, J., Baculi, F., Gingrich, D. E., and Shen, T. Y. (1995) Inhibition of mmetalloproteinase by futoenone derivatives. Bioorg. Med. Chem. Lett. 5, 1637–1642.CrossRefGoogle Scholar
  91. 91.
    Sun, H. H., Kaplita, P. V., Houck, D. R., Stawicki, M. B., McGarry, R., Wahl, R. C., Gillum, A. M., and Cooper R. (1996) Metalloproteinase inhibitor from doliocarpus verruculosus. Phytother. Res. 10, 194–197.CrossRefGoogle Scholar
  92. 92.
    Lee, H.-J., Chung, M.-C., Lee, C.-H., Yun, B.-S., Chun, H.-K., and Kho, Y.-H. (1996) Gelastatins A and B, new inhibitors of gelatinase A from Westerdykella multispora F50733. J. Antibiot. 50, 357–359.CrossRefGoogle Scholar
  93. 93.
    Bols, M., Binderup, L., Hansen, J., and Rasmussen, P. (1992) Inhibition ofcollagenase by aranciamycin and aranciamycin derivatives. J. Med. Chem. 35, 2768–2771.PubMedCrossRefGoogle Scholar
  94. 94.
    Suomalainen, K., Sorsa, T., Golub, L. M., Ramamurthy, N., Lee, H.-M., Uitto, V.-J., Saari, H., and Konttinen, Y. (1992) Specificity of the anticollagenase action of tetracyclines: relevance to their antiinflammatory potential. Antimicrob. Agents Chemother. 36, 227–229.PubMedCrossRefGoogle Scholar
  95. 95.
    Reich, R., Thompson, E. W., Iwamoto, Y., Martin, G. R., Deason, J. R., Fuller, G. C., and Miskin, R. (1988) Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res. 48, 3307–3312.PubMedGoogle Scholar
  96. 96.
    Schultz, R. M., Silberman, S., Persky, B., Bajkowski, A. S., and Carmichael, D. F. (1988) Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B 16–F 10 melanoma cells. Cancer Res. 48, 5539–5545.PubMedGoogle Scholar
  97. 97.
    Alvarez, O. A., Carmichael, D. F., and DeClerck, Y. A. (1990) Inhibition of collagenolytic activity and metastasis of tumour cells by a recombinant human tissue inhibitor of metalloproteinases. J. Natl. Cancer. Inst. 82 589–595Google Scholar
  98. 98.
    Eccles, S. A., Box, G. M., Court, W. J., Bone, E. A., Thomas, W., and Brown, P. D. (1996) Control of lymphatic and hematogenous metastases of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). Cancer Res. 56, 2815–2822.PubMedGoogle Scholar
  99. 99.
    Wang, X., Fu, X., Brown, P. D., Crimmin, M. J., and Hoffman, R. M. (1994) Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumour growth and spread in a patient-like orthotopic model in nude mice. Cancer Res. 54, 4726–4728.PubMedGoogle Scholar
  100. 100.
    An, Z., Wang, X., Willmott, N., Chander, S. K., Tickle, S., Docherty, A. J. P., et al. (1997) Conversion of a highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. Clin. Exp. Metastasis 15, 184–195.PubMedCrossRefGoogle Scholar
  101. 101.
    Sledge, G. W., Qulali, M., Goulet, R., Bone, E. A., and Fife, R. (1995) Effect ofmatrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J. Natl. Cancer Res. 87, 1546–1550.CrossRefGoogle Scholar
  102. 102.
    Anderson, I. C., Shipp, M. A., Docherty, A. J. P., and Teicher, B. A. (1996) Combination therapy including a gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine Lewis lung carcinoma. Cancer Res. 56, 715–710.Google Scholar
  103. 103.
    Davies, B., Brown, P. D., East, N., Crimmin, M. J., and Balkwill, F. R. (1993) A synthetic matrix metalloproteinase inhibitor decreases tumour burden and prolongs survival of mice bearing human ovarian carcinoma xenograft. Cancer Res. 53, 2087–2091.PubMedGoogle Scholar
  104. 104.
    DeClerck, Y. A., Perez, N., Shimada, H., Boone, T. C., Langley, K. E., and Taylor, S. M. (1992) Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res. 52, 701–708.Google Scholar
  105. 105.
    Watson, S. A., Morris, T. M., Robinson, G., Crimmin, M., Brown, P. D., and Hardcastle, J. D. (1995) Inhibition of organ invasion by metalloproteinase inhibitor, BB-94 (batimastat) in two human colon metastasis models. Cancer Res. 55, 3629–3633.PubMedGoogle Scholar
  106. 106.
    Conway, J. G., Trexler, S. J., Wakefield, J. A., Marron, B. E., Emerson, D. L., Bickett, D. M., et al. (1996) Effect of matrix metalloproteinase inhibitors on tumour growth and spontaneous metastasis. Clin. Exp. Metastasis 14, 115–124.PubMedCrossRefGoogle Scholar
  107. 107.
    Jain, R. K. (1994) Barriers to drug delivery in solid tumours. Sci. Am. 271, 58–65.PubMedCrossRefGoogle Scholar
  108. 108.
    Folkman, J. (1996) New perspectives in clinical oncology from angiogenesis research. Eur. J. Cancer 32A, 2535–2539.CrossRefGoogle Scholar
  109. 109.
    Stahle-Backdahl, M., Sandstedt, B., Bruce, K., Lindhal, A., Jimenez, M. G., Vega, J. A., and Lopez-Otin, C. (1997) Collagenase-3 (MMP-13) is expressed during human fetal ossifiication and re-expressed in post-natal bone remodelling and in rheumatoid arthritis. Lab. Invest. 76, 717–728.PubMedGoogle Scholar
  110. 110.
    Mitchell, P. G., Magna, H. A., Reeves, L. M., Loprestimorrow, L. L., Yocum, S. A., Rosner, P. J., Geoghegan, K. F., and Hambor, J. E. (1996) Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteroarthritic cartilage. J. Clin. Invest. 97, 761–768.Google Scholar
  111. 111.
    Elliot, M. J., Maini, R. N., Feldmann, M., Kalden, J. R., Antoni, C., Smolen, J. S., et al. (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110.CrossRefGoogle Scholar
  112. 112.
    Wood, N. D., Aitken, M., Harris, S., Kitchener, S., Mcclelland, G. R., and Sharp, S. (1996) Tolerability and pharmacokinetics of the cartilage protective agent (R032–3555) in healthy male volunteers. Br. J. Clin. Pharmacol. 42, 676, 677.Google Scholar
  113. 113.
    Gijbels, K., Proost, P., Masure, S., Carton, H., Billiau, H., and Opdenakker, G. (1993) Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. J. Neurosci. Res. 36, 432–440.PubMedCrossRefGoogle Scholar
  114. 114.
    Hewson, A. K., Smith, T., Leonard, J. P., and Cuzner, M. L. (1995) Suppression of exprimental allergic encephalomyelitis in the Lewis rat by the matrix metalloproteinase inhibitor RO31–9790. Inflamm. Res. 44, 345–349.Google Scholar
  115. 115.
    Clements, J. M., Cossins, J. A., Wells, G. M. A., Corkill, D. J., Helfrich, K., Wood, L. M., et al. (1997) Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-a inhibitor. J. Neuroimm. 74, 85–94.CrossRefGoogle Scholar
  116. 116.
    Kuroda, Y. and Shimamoto, Y. (1991) Human tumour necrosis factor-alpha augments experimental allergic encephalomyelitis in rats. J. Neuroimmunol. 34, 159–164.PubMedCrossRefGoogle Scholar
  117. 117.
    Baker, D., Butler, D., Scallon, B. J., O’Neill, J. K., Turk, J. L., and Feldmann, M. (1994) Control of established experimental allergic encephalomyelitis by inhibition of tumour necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins. Eur. J. Immunol. 24, 2040–2048.PubMedCrossRefGoogle Scholar
  118. 118.
    Rosenberg, G. A. and Navratil, M. (1997) Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 48, 921–926.PubMedCrossRefGoogle Scholar
  119. 119.
    Guarda, E., Katwa, L. C., Campbell, S. E., Tanner, M. A., Webel, R. M., Laughlin, H., Jenkins, S., and Myers, P. R. (1996) Extracellular matrix collagen synthesis and degradation following coronary balloon angioplasty. J. Mol. Cell. Cardiol. 28, 699–706.PubMedCrossRefGoogle Scholar
  120. 120.
    Nikkari, S. T., Geary, R. L., Hatsukami, T., Ferguson, M., Forough, R., Alpers, C. E., and Clowes, A. W. (1996) Expression of collagen, interstitial collagenase, and tissue inhibitor of metalloproteinases1 in restenosis after carotid endarterectomy. Am. J. Pathol. 148, 777–783.PubMedGoogle Scholar
  121. 121.
    Finlay, G. A., Odriscoll, L. R., Russell, K. J., Darcy, E. M., Masterson, J. B., Fitzgerald, M. X., and O’Connor, C. M. (1997) Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. Resp. Crit. Care Med. 156, 240–247.PubMedCrossRefGoogle Scholar
  122. 122.
    Ohmiya, N., Saga, S., Ohbayashi, M., Kozaki, K., Miyaishi, O., Kobayashi, M., et al. (1997) Kinetics and collagenolytic role of eosinophils in chronic gastric ulcer in the rat. Histochem. Cell Biol. 108, 27–34.PubMedCrossRefGoogle Scholar
  123. 123.
    Bailey, C. J., Hembry, R. M., Alexander, A., Irving, M. H., Grant, M. E., and Shuttleworth, C. A. (1994) Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn’s disease and normal intestine. J. Clin. Pathol. 47, 113–116.PubMedCrossRefGoogle Scholar
  124. 124.
    Mignatti, P., Tsuboi, R., Robbins, E., and Rifkin, D. B. (1989) In vitro angiogenesis on the human amniotic membrane: requirements for basic fibroblast growth factor-induced proteinases. J. Cell Biol. 108, 671–682.PubMedCrossRefGoogle Scholar
  125. 125.
    Mikkelsen, T., Yan, P. S., Ho, K. L., Sameni, M., Sloane, B. F., and Rosenblum, M. L. (1995) Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. J. Neurosurg. 83, 285–290.PubMedCrossRefGoogle Scholar
  126. 126.
    Sinha, A. A., Gleason, D. F., Staley, N. A., Wilson, M. J., Sameni, M., and Sloane, B. F. (1995) Cathepsin B in angiogenesis of human prostate: an immunohistochemical and immunoelectron microscopic analysis. Anat. Record 241, 353–362.CrossRefGoogle Scholar
  127. 127.
    Taraboletti, G., Garofalo, A., Belotti, D., Drudis, T., Borsotti, P., Scanziani, E., Brown, P., and Giavazzi, R. (1995) Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J. Natl. Cancer Inst. 87, 293–298.PubMedCrossRefGoogle Scholar
  128. 128.
    Moses, M. A., Sudhalter, J., and Langer, R. (1990) Identification of an inhibitor of neovascularization from cartilage. Science 248, 1408–1410.PubMedCrossRefGoogle Scholar
  129. 129.
    Murphy, A. N., Unsworth, E. J., and Stetler-Stevenson, W. G. (1993) Tissue inhibitor ofmmetalloproteinases2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J. Cell. Physiol. 157, 351–358.Google Scholar
  130. 130.
    Johnson, M. D., Kim, H. R., Chesler, L., Tsao-Wu, G., Bouck, N., and Polverini, P. J. (1994) Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J. Cell. Physiol. 160, 194–202.PubMedCrossRefGoogle Scholar
  131. 131.
    Karelina, T. V., Goldberg, G. I., and Eisen, A. Z. (1995) Matrix metalloproteinases in blood vessel development in human fetal skin and in cutaneous tumors. J. Invest. Dermatol. 105, 411–417.PubMedCrossRefGoogle Scholar
  132. 132.
    Rao, J. S., Sawaya, R., Gokaslan, Z. L. Yung, W. K. A., Goldstein, G. W., and Laterra, J. (1996) Modulation of serine proteinases and metalloproteinases during morphogenic glial-endothelial interactions. J. Neurochem. 66, 1657–1664.Google Scholar
  133. 133.
    Pepper, M. S., Montesano, R., Mandriota, S. J., Orci, L., and Vassalli, J. D. (1996) Angiogenesis: a paradigm for balanced extracellular proteolysis during cell migration and morphogenesis. Enz. Prot. 49, 138–162.Google Scholar

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© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Peter D. Brown
  • Mark Whittaker

There are no affiliations available

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