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STI571: A gene product-targeted therapy for leukemia

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Abstract

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem-cell disorder characterized by the (9:22) translocation and resultant production of the constitutively activated bcr-abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem-cell transplantation, with stem-cell transplantation being the only curative therapy. Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product-targeted therapy, offering new hope for expanded treatment options for patients with CML.

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References and Recommended Reading

  1. Nowell PC, Hungerford DA: A minute chromosome in human chronic granulocytic leukemia. Science 1960, 132:1497–1501.

    Google Scholar 

  2. Rowley JD: A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973, 243:290–293.

    Article  PubMed  CAS  Google Scholar 

  3. de Klein A, van Kessel AG, Grosveld G, et al.: A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1982, 300:765–767.

    Article  PubMed  Google Scholar 

  4. Heisterkamp N, Stephenson JR, Groffen J, et al.: Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 1983, 306:239–242.

    Article  PubMed  CAS  Google Scholar 

  5. Shtivelman E, Lifshitz B, Gale RP, Canaani E: Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 1985, 315:550–554.

    Article  PubMed  CAS  Google Scholar 

  6. Heisterkamp N, Stam K, Groffen J, et al.: Structural organization of the bcr gene and its role in the Ph’ translocation. Nature 1985, 315:758–761.

    Article  PubMed  CAS  Google Scholar 

  7. Abelson HT, Rabstein LS: Lymphosarcoma: virus-induced thymic-independent disease in mice. Cancer Res 1970, 30:2213–2222.

    PubMed  CAS  Google Scholar 

  8. Witte ON, Dasgupta A, Baltimore D: Abelson murine leukaemia virus protein is phosphorylated in vitro to form phosphotyrosine. Nature 1980, 283:826–831.

    Article  PubMed  CAS  Google Scholar 

  9. Witte ON, Goff S, Rosenberg N, Baltimore D: A transformationdefective mutant of Abelson murine leukemia virus lacks protein kinase activity. Proc Natl Acad Sci U S A 1980, 77:4993–4997.

    Article  PubMed  CAS  Google Scholar 

  10. Lugo TG, Pendergast AM, Muller AJ, Witte ON: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990, 247:1079–1082.

    Article  PubMed  CAS  Google Scholar 

  11. McLaughlin J, Chianese E, Witte ON: In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A 1987, 84:6558–6562.

    Article  PubMed  CAS  Google Scholar 

  12. Gishizky ML, Witte ON: Initiation of deregulated growth of multipotent progenitor cells by bcr-abl in vitro. Science 1992, 256:836–839.

    Article  PubMed  CAS  Google Scholar 

  13. Daley GQ, Van Etten RA, Baltimore D: Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990, 247:824–830.

    Article  PubMed  CAS  Google Scholar 

  14. Heisterkamp N, Jenster G, ten Hoeve J, et al.: Acute leukaemia in bcr/abl transgenic mice. Nature 1990, 344:251–253.

    Article  PubMed  CAS  Google Scholar 

  15. Neshat MS, Raitano AB, Wang HG, et al.: The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: roles for phosphatidylinositol 3-kinase and Raf. Mol Cell Biol 2000, 20:1179–1186.

    Article  PubMed  CAS  Google Scholar 

  16. Horita M, Andreu EJ, Benito A, et al.: Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. J Exp Med 2000, 191:977–984.

    Article  PubMed  CAS  Google Scholar 

  17. Bazzoni G, Carlesso N, Griffin JD, Hemler ME: Bcr/Abl expression stimulates integrin function in hematopoietic cell lines. J Clin Invest 1996, 98:521–528.

    PubMed  CAS  Google Scholar 

  18. Senechal K, Heaney C, Druker B, Sawyers CL: Structural requirements for function of the Crkl adapter protein in fibroblasts and hematopoietic cells. Mol Cell Biol 1998, 18:5082–5090.

    PubMed  CAS  Google Scholar 

  19. Yaish P, Gazit A, Gilon C, Levitzki A: Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 1988, 242:933–935.

    Article  PubMed  CAS  Google Scholar 

  20. Kaur G, Gazit A, Levitzki A, et al.: Tyrphostin induced growth inhibition: correlation with effect on p210bcr-abl autokinase activity in K562 chronic myelogenous leukemia. Anticancer Drugs 1994, 5:213–222.

    Article  PubMed  CAS  Google Scholar 

  21. Anafi M, Gazit A, Zehavi A, et al.: Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate. Blood 1993, 82:3524–3529.

    PubMed  CAS  Google Scholar 

  22. Druker BJ, Tamara S, Buchdunger E, et al.: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996, 2:561–566.

    Article  PubMed  CAS  Google Scholar 

  23. Deininger MW, Goldman JM, Lydon N, Melo JV: The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997, 90:3691–3698.

    PubMed  CAS  Google Scholar 

  24. Marley SB, Deininger MW, Davidson RJ, et al.: The tyrosine kinase inhibitor STI571, like interferon-alpha, preferentially reduces the capacity for amplification of granulocytemacrophage progenitors from patients with chronic myeloid leukemia. Exp Hematol 2000, 28:551–557.

    Article  PubMed  CAS  Google Scholar 

  25. Kasper B, Fruehauf S, Schiedlmeier B, et al.: Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor: activity on lineage-committed and primitive chronic myelogenous leukemia progenitors. Cancer Chemother Pharmacol 1999, 44:433–438.

    Article  PubMed  CAS  Google Scholar 

  26. Gambacorti-Passerini C, le Coutre P, Mologni L, et al.: Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 1997, 23:380–394.

    Article  PubMed  CAS  Google Scholar 

  27. Carroll M, Ohno-Jones S, Tamura S, et al.: CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997, 90:4947–4952.

    PubMed  CAS  Google Scholar 

  28. Beran M, Cao X, Estrov Z, et al.: Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res 1998, 4:1661–1672.

    PubMed  CAS  Google Scholar 

  29. le Coutre P, Mologni L, Cleris L, et al.: In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999, 91:163–168.

    Article  PubMed  Google Scholar 

  30. Druker BJ, Talpaz M, Resta D, et al.: Clinical efficacy and safety of a Abl specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia [abstract]. Blood 1999, 94:368a. The results of the first clinical trials with STI571 in chronic-phase CML patients who had failed interferon therapy.

    Google Scholar 

  31. Talpaz M, Sawyers CL, Kantarjain H, et al.: Activity of an ABL specific tyrosine kinase inhibitor in patients with Bcr-Abl positive acute leukemias, including chronic myelogenous leukemia in blast crisis [abstract]. Proc ASCO 2000, 18:4a. An update on the results with STI571 in patients with CML in blast crisis and Ph-positive ALL.

    Google Scholar 

  32. le Coutre P, Tassi E, Varella-Garcia M, et al.: Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000, 95:1758–1766.

    PubMed  Google Scholar 

  33. Mahon FX, Deininger MW, Schultheis B, et al.: 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.

    PubMed  CAS  Google Scholar 

  34. Gambacorti-Passerini C, Barni R, le Coutre P, et al.: Role of alpha1 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.

    Article  PubMed  CAS  Google Scholar 

  35. Druker BJ, Lydon NB: Lessons learned from the development of an Abl kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000, 105:3–7. A review of the development of STI571 from bench to bedside.

    Article  PubMed  CAS  Google Scholar 

  36. Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ: Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other anti-leukemic agents against Bcr-Abl-positive cells. Blood 2000, 96:3195–3199. See annotation for reference [37].

    PubMed  CAS  Google Scholar 

  37. Fang G, Kim CN, Perkins CL, et al.: CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl positive human leukemia cells to apoptosis due to antileukemic drugs. Blood 2000, 96:2246–2253. These two articles provide the preclinical rationale for combination studies of STI571 with a variety of antileukemic agents, including interferon, Ara-C, and daunorubicin.

    PubMed  CAS  Google Scholar 

  38. Melo JV: The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood 1996, 88:2375–2384.

    PubMed  CAS  Google Scholar 

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Mauro, M.J., Druker, B.J. STI571: A gene product-targeted therapy for leukemia. Curr Oncol Rep 3, 223–227 (2001). https://doi.org/10.1007/s11912-001-0054-z

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