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DOI: 10.1055/s-2002-20427
Der selektive Tyrosinkinase-Inhibitor Imatinib (STI571) bei hämatologischen und onkologischen Erkrankungen
Selective tyrosinekinase inhibitor imatinib (STI571) in haematological and oncological diseasePublication History
Manuskript-Eingang: 27. Dezember 2001
Annahme nach Revision: 06. Februar 2002
Publication Date:
28 February 2002 (online)
![](https://www.thieme-connect.de/media/dmw/200209/lookinside/thumbnails/10.1055-s-2002-20427-1.jpg)
Proteinkinasen sind eine große Familie homologer Proteine, die aus zwei Subfamilien, den Serin-Threonin-Kinasen und den Tyrosinkinasen, besteht. Sie sind Teil der Signaltransduktionswege und spielen eine zentrale Rolle in verschiedenen biologischen Prozessen, wie Zellwachstum, Stoffwechsel, Differenzierung und Apoptose. Tyrosinkinasen binden ATP und übertragen Phosphatgruppen von ATP auf Tyrosinreste verschiedener Substrate. Imatinib (Glivec®, früher STI571 oder CGP57148B) ist ein selektiver Inhibitor der strukturell ähnlichen Tyrosinkinasen ABL, PDGF-R und c-kit ([Abb. 1] und [2] ).
Literatur
- 1 Apperley J F, Schultheis B, Chase A. et al . Chronic myeloproliferative diseases with t(5;12) and a PDGFRb fusion gene: Complete cytogenetic remissions on STI571. Blood. 2001; 98 (Suppl 1) 726a
- 2 Barthe C, Cony-Makhoul P, Melo J V, Reiffers J, Mahon F X. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001; 293 2163a
- 3 Beham Schmid C, Apfelbeck U, Sill H, Tsybrovsky O, Hofler G, Haas O A, Linkesch W. Treatment of chronic myelogenous leukemia with the tyrosine kinase inhibitor STI571 results in marked regression of bone marrow fibrosis. Blood. 2002; 99 381-383
- 4 Brouard M, Saurat J H. Cutaneous reactions to STI571. N Engl J Med. 2001; 345 618-619
- 5 Buchdunger E, Cioffi C L, Law N, Stover D, Ohno-Jones S, Druker B J, Lydon N B. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000; 295 139-145
- 6 Deininger M WN, Goldman J M, Lydon N, Melo J V. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997; 90 3691-3698
- 7 Druker B J, Kantarjian H M, Talpaz M, Paquette R, Mauro M J, Rosamilia M, Zoellner U, Resta D, Capdeville R, Sawyers C L. A phase I study of Gleevec (imatinib mesylate) administered concomitantly with cytosine arabinoside (Ara-C) in patients with Philadelphia positive chronic myeloid leukemia (CML). Blood. 2001; 98 (Suppl 1) 845a-846a
- 8 Druker B J, Lydon N B. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000; 105 3-7
- 9 Druker B J, Sawyers C L, Kantarjian H, Resta D J, Fernandez Reese S, Ford J M, Capdeville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001; 344 1038-1042
- 10 Druker B J, Talpaz M, Resta D J, Peng B, Buchdunger E, Ford J M, Lydon N B, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers C L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344 1031-1037
- 11 Druker B J, Tamura S, Buchdunger E, Ohno S, Segal G M, Fanning S, Zimmermann J, Lydon N B. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Medic. 1996; 2 561-566
- 12 Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, Rossi F, Gianazza E, Brueggen J, Cozens R, Piotelli P, Pogliani E, Corneo G, Formelli F, D’Incalci M. Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemic cells to the Abl inhibitor STI571. J Natl Cancer Inst. 2000; 92 1641-1650
- 13 Gambacorti-Passerini C, le C outre P, Mologni L, Fanelli M, Bertazzoli C, Marchesi E, Di Nicola M, Biondi A, Corneo G M, Belotti D, Pogliani E, Lydon N B. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Diseases. 1997; 23 380-394
- 14 Gorre M E, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P N, Sawyers C L. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293 876-880
- 15 Hehlmann R, Hochhaus A. Evidenzbasierte Therapie der chronischen myeloischen Leukämie. Dtsch Ärztebl. 2001; 98 A1834-A1837
- 16 Heinrich M C, Griffith D J, Druker B J, Wait C L, Ott K A, Zigler A J. Inhibition of c-kit receptor tyrosine kinase activity by STI571, a selective tyrosine kinase inhibitor. Blood. 2000; 96 925-932
- 17 Hochhaus A, Kreil S, Corbin A, La Rosée P, Lahaye T, Berger U, Cross N CP, Linkesch W, Druker B J, Hehlmann R. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001; 293 2163a
- 18 Joensuu H, Roberts P J, Sarlomo-Rikala M, Andersson L C, Tervahartiala P, Tuveson D, Silberman S L, Capdeville R, Dimitrijevic S, Druker B, Demetri G D. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001; 344 1052-1056
- 19 Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood. 2001; 97 1999-2007
- 20 Kantarjian H M, Sawyers C L, Hochhaus A, Guilhot F, Schiffer C A, Deininger M W, Gambacorti-Passerini C, Stone R M, Goldman J, Fischer T, Rosamilia M, Zoellner U, Resta D, Capdeville R, Druker B J. GleevecTM (Imatinib mesylate) induced hematologic and cytogenetic responses confirmed and expanded in patients with chronic myeloid leukemia (CML) - A phase II study update. Blood. 2001; 98 (Suppl 1) 845a
- 21 Kilic T, Alberta J A, Zdunek P R, Acar M, Iannarelli P, O’Reilly T, Buchdunger E, Black P M, Stiles C. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Research. 2000; 60 5143-5150
- 22 Kreil S, Müller M C, Lahaye T, La Rosée P, Corbin A M, Schoch C, Cross N CP, Berger U, Rieder H, Druker B J, Gschaidmeier H, Hehlmann R, Hochhaus A. Molecular and chromosomal mechanisms of resistance in CML patients after STI571 (Glivec) therapy. Blood. 2001; 98 (Suppl1) 435a
- 23 Krystal G W, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res. 2000; 6 3319-3326
- 24 Mahon F X, Deininger M WN, Schultheis B, Chabrol J, Reiffers J, Golfdman J M, Melo J V. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000; 96 1070-1079
- 25 Merx K, Kreil S, Lahaye T, Müller M C, Paschka P, Schoch C, Weisser A, Kuhn C, Landmann T, Gschaidmeier H, Berger U, Hehlmann R, Hochhaus A. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response to STI571 in chronic phase CML patients. Blood. 2001; 98 (Suppl 1) 846a-847a
- 26 O’Brien S, Vallance S E, Craddock C, Holyoake T L, Goldman J M. the UK PISCES Group . PEGIntron and STI571 combination evaluation study (PISCES) in chronic phase chronic myeloid leukaemia. Blood. 2001; 98 (Suppl 1) 846a
- 27 O’Dwyer M E, Mauro M J, Kuyl J M, Paquette R, Sawyers C L, Druker B J. Preliminary evaluation of the combination of imatinib mesylate (Glevec) in combination with low dose interferon-alpha for the treatment of chronic phase CML. Blood. 2001; 98 (Suppl 1) 846a
- 28 Okuda K, Weisberg E, Gilliland D G, Griffin J D. ARG tyrosine kinase activity is inhibited by STI571. Blood. 2001; 97 2440-2448
- 29 Ottmann O G, Sawyers C, Druker B, Goldman J, O’Brien S G, Reiffers J, Silver R T, Tura S, Fischer T, Niederwieser D, Schiffer C, Baccarani M, Gratwohl A, Hochhaus A, Reese S F, Capdeville R. Phase II study of STI571 in adult patients with Philadelphia chromosome (Ph) positive acute leukaemias. Hematol J. 2001; 2 (Suppl 1) 93
- 30 Rubin B P, Singer S, Tsao C, Duensing A, Lux M L, Ruiz R, Hibbard M K, Chen C J, Xiao S, Tuveson D A, Demetri G D, Fletcher D M, Fletcher J A. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001; 61 8118-8121
- 31 Sawyers C L. Cancer treatment in the STI571 era: What will change?. J Clin Oncol. 2001; 19 (Suppl 1) 13s-16s
- 32 Sawyers C L, Hochhaus A, Feldman E, Goldman J M, Miller C, Ottmann O G, Schiffer C A, Talpaz M, Guilhot F, Niederwieser D, Ben-Am M, Gathmann I, Ford J, Druker B J. on behalf of the International Gleevec Study Group . Gleevec/Glivec (Imatinib mesylate, STI-571) in patients with chronic myeloid leukemia (CML) in myeloid blast crisis: Updated results of a phase II study. Blood. 2001; 98 (Suppl 1) 845a
- 33 Silver R T, Woolf S H, Hehlmann R, Appelbaum F R, Anderson J, Bennett C, Goldman J M, Guilhot F, Kantarjian H M, Lichtin A E, Talpaz M, Tura S. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: Developed for the American Society of Hematology. Blood. 1999; 94 1517-1536
- 34 Talpaz M, Silver R T, Druker B, Paquette R, Goldman J M, G ambacorti-Passerini C, Guilhot F, Schiffer C A, Reese S F, Kantarjian H M, Ford J M. GleevecTM (formerly STI571): An active drug in patients with PH+ chronic myeloid leukemia in accelerated phase - updated results of a phase II study. Blood. 2001; 98 (Suppl 1) 845a
- 35 Thiesing J T, Ohno-Jones S, Kolibaba K S, Druker B J. Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood. 2000; 96 3195-3199
- 36 Topaly J, Zeller W, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positivbe chronic myelogenous leukemia cells. Leukemia. 2001; 15 342-347
- 37 van Oosterom A T, Judson I, Verweij J, Stroobants S, di Paola E D, Dimitrijevic S, Martens M, Webb A, Sciot R, van Glabbeke M, Silberman S, Nielsen O S, for t he European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001; 358 1421-1423
- 38 Weisberg E, Griffin J D. Mechanism of resistence to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood. 2000; 95 3498-3505
Korrespondenz
Priv.-Doz. Dr. med. Andreas Hochhaus
III. Medizinische Universitätsklinik, Fakultät
für Klinische Medizin Mannheim der Universität
Heidelberg
Wiesbadener Straße 7-11
68305 Mannheim
Phone: 0621/3832854
Fax: 0621/3833833
Email: hochhaus@uni-hd.de