Download PDF
Dtsch Med Wochenschr 2004; 129(8): 391-395
DOI: 10.1055/s-2004-819899
Übersichten
Pathophysiologie / Onkologie
© Georg Thieme Verlag Stuttgart · New York

Proteasen in Malignomen

Bedeutung für Pathogenese und mögliche therapeutische KonsequenzenProteases in malignant tumorsTheir significance for the pathogenesis and possible therapeutic applicationsE. Fröhlich1
  • 1Anatomisches Institut, Universität Tübingen
Further Information

Publication History

eingereicht: 26.6.2003

akzeptiert: 7.11.2003

Publication Date:
11 February 2004 (online)

Also available at
    Permissions and Reprints

Proteasen sind an einer Fülle von Stoffwechselvorgängen insbesondere bei Gerinnung, Entzündung, Entwicklung und Apoptose beteiligt. Auch bei zahlreichen Erkrankungen spielen sie in der Pathogenese eine entscheidende Rolle. So sind einige erbliche Erkrankungen bekannt, die auf erhöhter Proteaseaktivität beruhen. Am bekanntesten sind das Lungenemphysem (α-1-Antitrypsin-Inhibitor Defekt, 14) und das angioneurotische Ödem (C1-Esterase-Inhibitor Defekt, 4). Allerdings sind diese Erkrankungen eher selten. Wesentlich häufiger sind nicht erblich bedingte Veränderungen der Proteaseaktivität, beispielsweise bei rheumatischen Erkrankungen und bei Malignomen. Im Folgenden soll insbesondere auf die Rolle der Proteasen im Malignomgeschehen eingegangen werden. Die selektive Hemmung bestimmter Proteaseaktivitäten stellt prinzipiell eine Therapiemöglichkeit für Malignome dar. Leider haben derartige Therapieversuche bislang nicht den gewünschten Erfolg gebracht. Im Folgenden soll dargestellt werden, wo die Probleme und Chancen eines Eingriffs in das Proteasesystem bei Tumoren liegen.

Proteasen werden nach verschiedenen Gesichtspunkten eingeteilt: nach

Art der Spaltung im Protein (Abspaltung vom aminoterminalen oder vom carboxyterminalen Ende des Proteins), der topographischen Verteilung des Enzyms in der Zelle (im Zytosol, membranassoziiert oder in Lysosomen enthalten), dem aktiven Zentrum.

Letztere Einteilung ist im Hinblick auf Funktion und Inhibition der Proteasen besonders zweckmäßig und wird daher bevorzugt verwendet.

Literatur

  • 1 Adams J. Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer.  Curr Opin Chem Biol. 2002;  6 493-500
    Search in Google Scholar
  • 2 Beattie G, Smyth J. Phase I study of intraperitoneal metalloproteinase inhibitor BB94 in patients with malignant ascites.  Clin Cancer Res. 1998;  4 1899-1902
    Search in Google Scholar
  • 3 Bochtler M, Ditzel L, Groll M, Hartmann C, Huber R. The proteasome.  Annu Rev Biophys Biomol Struct. 1999;  28 295-317
    Search in Google Scholar
  • 4 Bond W J, Herrod H, Duberstein L. Hereditary angioedema: association with IgA deficiency and otolaryngologic disorders.  Laryngoscope. 1981;  91 416-421
    Search in Google Scholar
  • 5 Bonomi P. Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer.  Semin Oncol. 2002;  29 78-86
    Search in Google Scholar
  • 6 Bose S, Mason G, Rivett A. Phosphorylation of proteasomes in mammalian cells.  Mol Biol Rep. 1999;  26 11-14
    Search in Google Scholar
  • 7 Bramhall S. The matrix metalloproteinases and their inhibitors in pancreatic cancer. From molecular science to a clinical application.  Int J Pancreatol. 1997;  21 1-12
    Search in Google Scholar
  • 8 Cater S, Lees W, Hill J, Brzin J, Kay J, Phylip L. Aspartic proteinase inhibitors from tomato and potato are more potent against yeast proteinase A than cathepsin D.  Biochim Biophys Acta. 2002;  1596 76-82
    Search in Google Scholar
  • 9 Coussens L, Fingleton B, Matrisian L. Matrix metalloproteinase inhibitors and cancer: trials and tribulations.  Science. 2002;  295 2387-2392
    Search in Google Scholar
  • 10 Cuervo A, Dice J. Lysosomes, a meeting point of proteins, chaperones, and proteases.  J Mol Med. 1998;  76 6-12
    Search in Google Scholar
  • 11 Dano K, Andreasen P, Grondahl-Hansen J, Kristensen P, Nielsen L, Skriver L. Plasminogen activators, tissue degradation, and cancer.  Adv Cancer Res. 1985;  44 139-266
    Search in Google Scholar
  • 12 DeClerck Y. Interactions between tumour cells and stromal cells and proteolytic modification of the extracellular matrix by metalloproteinases in cancer.  Eur J Cancer. 2000;  36 1258-1268
    Search in Google Scholar
  • 13 Evans J, Stark A, Johnson C. et al . A phase II trial of marimastat in advanced pancreatic cancer.  Br J Cancer. 2001;  85 1865-1870
    Search in Google Scholar
  • 14 Gadek J, Klein H, Holland P, Crystal R. Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects.  J Clin Invest. 1981;  68 1158-1165
    Search in Google Scholar
  • 15 Ghadimi B, Schlag P. Tumor metastasis. Molecular principles and therapeutic options.  Chirurg. 1998;  69 1315-1322
    Search in Google Scholar
  • 16 Giavazzi R, Garofalo A, Ferri C. et al . Batimastat, a synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts.  Clin Cancer Res. 1998;  4 985-992
    Search in Google Scholar
  • 17 Hirvonen R, Talvensaari-Mattila A, Paakko P, Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 (MMP-2) in T(1-2)N0 breast carcinoma.  Breast Cancer Res Treat. 2003;  77 85-91
    Search in Google Scholar
  • 18 Janicke F, Schmitt M, Pache L. et al . Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer.  Breast Cancer Res Treat. 1993;  24 195-208
    Search in Google Scholar
  • 19 Katunuma N, Tsuge H, Nukatsuka M, Asao T, Fukushima M. Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells.  Arch Biochem Biophys. 2002;  397 305-311
    Search in Google Scholar
  • 20 Koblinski J, Ahram M, Sloane B. Unraveling the role of proteases in cancer.  Clin Chim Acta. 2000;  291 113-135
    Search in Google Scholar
  • 21 Kolkhorst V, Sturzebecher J, Wiederanders B. Inhibition of tumour cell invasion by protease inhibitors: correlation with the protease profile.  J Cancer Res Clin Oncol. 1998;  124 598-606
    Search in Google Scholar
  • 22 LeBlanc R, Catley L, Hideshima T. et al . Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.  Cancer Res. 2002;  62 4996-5000
    Search in Google Scholar
  • 23 Leto G, Pizzolanti G, Tumminello F, Gebbia N. Effects of E-64 (cysteine-proteinase inhibitor) and pepstatin (aspartyl-proteinase inhibitor) on metastasis formation in mice with mammary andovarian tumors.  In Vivo. 1994;  8 231-236
    Search in Google Scholar
  • 24 Macaulay V, O’Byrne K, Saunders M. et al . Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions.  Clin Cancer Res. 1999;  5 513-520
    Search in Google Scholar
  • 25 Mitsiades N, Mitsiades C, Richardson P. et al . The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications.  Blood. 2003;  101 2377-2380
    Search in Google Scholar
  • 26 Navab R, Mort J, Brodt P. Inhibition of carcinoma cell invasion and liver metastases formation by the cysteine proteinase inhibitor E-64.  Clin Exp Metastasis. 1997;  15 121-129
    Search in Google Scholar
  • 27 Ng R, Kellen J. The role of plasminogen activators in metastasis.  Med Hypotheses. 1983;  10 291-293
    Search in Google Scholar
  • 28 Orlowski R, Stinchcombe T, Mitchell B. et al . Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.  J Clin Oncol. 2002;  20 4420-4427
    Search in Google Scholar
  • 29 Parsons S, Watson S, Steele R. Phase I/II trial of batimastat, a matrix metalloproteinase inhibitor, in patients with malignant ascites.  Eur J Surg Oncol. 1997;  23 526-531
    Search in Google Scholar
  • 30 Pepper M. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis.  Arterioscler Thromb Vasc Biol. 2001;  21 1104-1117
    Search in Google Scholar
  • 31 Pray T, Parlati F, Huang J. et al . Cell cycle regulatory E3 ubiquitin ligases as anticancer targets.  Drug Resist Updat. 2002;  5 249-258
    Search in Google Scholar
  • 32 Quirt I, Bodurth A, Lohmann R. et al . Phase II study of marimastat (BB-2516) in malignant melanoma: A clinical and tumor biopsy study of the National Cancer Institute of Canada Clinical Trials Group.  Invest New Drugs. 2002;  20 431-437
    Search in Google Scholar
  • 33 Richardson P, Barlogie B, Berenson J. et al . A phase 2 study of bortezomib in relapsed, refractory myeloma.  N Engl J Med. 2003;  348 2609-2617
    Search in Google Scholar
  • 34 Rockway T. Small molecule inhibitors of urokinase-type plasminogen activator.  Expert Opinion on Therapeutic Patents. 2003;  13 773-786
    Search in Google Scholar
  • 35 Shepherd F, Giaccone G, Seymour L. et al . Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer.  J Clin Oncol. 2002;  20 4434-4439
    Search in Google Scholar
  • 36 Spyratos F, Maudelonde T, Brouillet J. et al . Cathepsin D: an independent prognostic factor for metastasis of breast cancer.  Lancet. 1989;  2 1115-1118
    Search in Google Scholar
  • 37 Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis.  Semin Cancer Biol. 2000;  10 415-433
    Search in Google Scholar
  • 38 Teicher B, Ara G, Herbst R, Palombella V, Adams J. The proteasome inhibitor PS-341 in cancer therapy.  Clin Cancer Res. 1999;  5 2638-2645
    Search in Google Scholar
  • 39 Thomssen C, Schmitt M, Goretzki L. et al . Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer.  Clin Cancer Res. 1995;  1 741-746
    Search in Google Scholar
  • 40 Van Noorden C, Jonges T, Van Marle J. et al . Heterogeneous suppression of experimentally induced colon cancer metastasis in rat liver lobes by inhibition of extracellular cathepsin B.  Clin Exp Metastasis. 1998;  16 159-167
    Search in Google Scholar
  • 41 Wald M, Olejar T, Sebkova V, Zadinova M, Boubelik M, Pouckova P. Mixture of trypsin, chymotrypsin and papain reduces formation of metastases and extends survival time of C57Bl6 mice with syngeneic melanoma B16.  Cancer Chemother Pharmacol. 2001;  47 S16-22
    Search in Google Scholar
  • 42 Wojtowicz-Praga S, Low J, Marshall J. et al . Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer.  Invest New Drugs. 1996;  14 193-202
    Search in Google Scholar
  • 43 Wright J, Hillsamer V, Gore-Langton R E, Cheson B D. Clinical trials referral resource. Current clinical trials for the proteasome inhibitor PS-341.  Oncology (Huntingt). 2000;  14 1589-1590, 1593-1594, 1597
    Search in Google Scholar
  • 44 Zwickl P, Voges D, Baumeister W. The proteasome: a macromolecular assembly designed for controlled proteolysis.  Philos Trans R Soc Lond B Biol Sci. 1999;  354 1501-1511
    Search in Google Scholar

Priv.-Doz. Dr. med. Eleonore Fröhlich

Anatomisches Institut, Eberhard-Karls-Universität Tübingen

Österbergstraße 3

72074 Tübingen