International Journal of Hematology

, Volume 79, Issue 5, pp 434–440 | Cite as

Imatinib Mesylate in Combination with Other Chemotherapeutic Agents for Chronic Myelogenous Leukemia

Article

Abstract

Imatinib therapy is an important contribution to the management of patients with chronic myelogenous leukemia (CML). Despite high rates of hematologic and cytogenetic responses to imatinib therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of CML. Experimental and clinical studies suggest that imatinib as a single drug may not be sufficient to eradicate BCR-ABL-positive stem cells. Therefore, whether combinations of imatinib with other agents can increase the length of molecular remission and whether such combinations can prolong survival should be determined by large-scale clinical studies. In this review, we discuss efficacious combinations for future clinical trials. These regimens combine imatinib with conventional chemotherapeutic agents or with inhibitors of other signal transduction molecules that may be preferentially activated in CML cells.

Key words

BCR-ABL Imatinib Tyrosine kinase CML Combination 

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References

  1. 1.
    Tauchi T, Broxmeyer HE. BCR/ABL signal transduction. Int J Hematol. 1995;61:105–112.CrossRefPubMedGoogle Scholar
  2. 2.
    Konopka JB, Watanabe SM, Witte ON. An alternation of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell. 1984;37:1035–1042.CrossRefPubMedGoogle Scholar
  3. 3.
    Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079–1082.CrossRefPubMedGoogle Scholar
  4. 4.
    Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330–1340.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207–219.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukemia in bcr/abl transgenic mice. Nature. 1990;344:251–253.CrossRefPubMedGoogle Scholar
  8. 8.
    Druker BJ, Tamura S, Buchdunger E, et al. Efficacy of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl-positive cells. Nat Med. 1996;2:561–566.CrossRefPubMedGoogle Scholar
  9. 9.
    Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopy-rimidine derivative. Cancer Res. 1996;56:100–104.PubMedGoogle Scholar
  10. 10.
    Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–932.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science. 2000;289:1938–1942.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell. 2003;112:831–843.CrossRefPubMedGoogle Scholar
  13. 13.
    Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 2003;4:75–85.CrossRefPubMedGoogle Scholar
  14. 14.
    Gambacorti-Passerini C, Barni R, le Coutre P, et al. 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.CrossRefPubMedGoogle Scholar
  15. 15.
    Gambacorti-Passerini C, le Coutre P, Zucchetti M, D’Incalci M. Binding of imatinib by α1-acid glycoprotein. Blood. 2002;100:367–368.CrossRefPubMedGoogle Scholar
  16. 16.
    Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther. 2003;304:1085–1092.CrossRefPubMedGoogle Scholar
  17. 17.
    Hegedus T, Orifi L, Seprodi A, Varadi A, Sarkadi B, Keri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochem Biophys Acta. 2002;1587:318–325.PubMedGoogle Scholar
  18. 18.
    Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–2373.CrossRefPubMedGoogle Scholar
  19. 19.
    Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–880.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gambacorti-Passerini C, Rossi F, Verga M, et al. Differences between in vivo and in vitro sensitivity to imatinib of Bcr-Abl+ cells obtained from leukemic patients. Blood Cells Mol Dis. 2002;28:361–372.CrossRefPubMedGoogle Scholar
  21. 21.
    Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2003;16:2190–2196.CrossRefGoogle Scholar
  22. 22.
    Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood. 2000;95:3498–3505.PubMedGoogle Scholar
  23. 23.
    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.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Sirulink A, Silver RT, Najfeld V. Marked ploidy and BCR-ABL gene amplification in vivo in a patient treated with STI571. Leukemia. 2001;15:1795–1797.CrossRefPubMedGoogle Scholar
  25. 25.
    Campbell LJ, Patsouris C, Rayeroux KC, Somana K, Januszewicz EH, Szer J. BCR/ABL amplification in chronic myelocytic leukemia blastic crisis following imatinib mesylate administration. Cancer Genet Cytogenet. 2002;139:30–33.CrossRefPubMedGoogle Scholar
  26. 26.
    Morel F, Le Bris MJ, Herry A, et al. Double minutes containing amplified bcr-abl fusion gene in a case of chronic myeloid leukemia treated by imatinib. Eur J Haematol. 2003;70:235–239.CrossRefPubMedGoogle Scholar
  27. 27.
    Tipping AJ, Mahon FX, Lagarde V, Goldman JM, Melo JV. Restoration of sensitivity to STI571 in STI571-resistant chronic myeloid leukemia cells. Blood. 2001;98:3864–3867.CrossRefPubMedGoogle Scholar
  28. 28.
    von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002;359:487–491.CrossRefGoogle Scholar
  29. 29.
    Hofmann WK, Jones LC, Lemp NA, et al. Ph+ acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood. 2002;99:1860–1862.CrossRefGoogle Scholar
  30. 30.
    Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002;99:3472–3475.CrossRefGoogle Scholar
  31. 31.
    Roche-Lestienne C, Soenen-Cornu V, Gradel-Duflos N, et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can preexist to the onset of treatment. Blood. 2002;100:1014–1018.CrossRefPubMedGoogle Scholar
  32. 32.
    Roumiantsev S, Shah NP, Gorre ME, et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci USA. 2002;99:10700–10705.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2:117–125.CrossRefPubMedGoogle Scholar
  34. 34.
    Ricci C, Scappini B, Divoky V, et al. Mutation in the ATP-binding pocket of the ABL kinase domain in an STI571-resistant BCR/ABL-positive cell line. Cancer Res. 2002;62:5995–5998.PubMedGoogle Scholar
  35. 35.
    Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611–4614.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276–283.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fang G, Kim CV, 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.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Thiesing JT, Ohno-Jones S, Kolibaba KS, et al. Efficacy of an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood. 2000;96:3195–3199.Google Scholar
  39. 39.
    Topaly J, Zeller WJ, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia. 2001;15:342–347.CrossRefGoogle Scholar
  40. 40.
    Druker BJ, Kantarjian H, Talpaz M, et al. A phase I study of Gleevec (imatinib mesylate) administered concomitantly with cytosine arabinoside (Ara-C) in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) [abstract]. Blood. 2001;98:845a.Google Scholar
  41. 41.
    Gardembas M, Rousselot P, Tulliez M, et al. Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood. 2003;102:4298–4305.CrossRefPubMedGoogle Scholar
  42. 42.
    Kano Y, Akutsu M, Tsunoda S, et al. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood. 2001;97:1999–2007.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    O’Dwyer ME, Mauro MJ, Kuyl J, Paquette R, Sawyers CL, Droker BJ. Preliminary evaluation of the combination of imatinib mesylate (Gleevec) in combination with low dose interferon-alpha for the treatment of chronic phase CML [abstract]. Blood. 2001;98:846a.Google Scholar
  44. 44.
    O’Brien SG, Vallance SE, Craddock C, Holyoake TL, Goldman JM, and the UK PISCES Group. PEGIntron and STI571 combination evaluation study (PISCES) in chronic phase chronic myeloid leukaemia [abstract]. Blood. 2001;98:846a.Google Scholar
  45. 45.
    Reichert A, Heisterkamp N, Daley GQ, Groffen J. Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood. 2001;97:1399–1403.CrossRefPubMedGoogle Scholar
  46. 46.
    Peters DG, Hoover RR, Gerlach MJ, et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood. 2001;97:1404–1412.CrossRefPubMedGoogle Scholar
  47. 47.
    Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood. 2002;100:1068–1071.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Brodsky AL. Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line. Blood. 2003;101:2070.CrossRefPubMedGoogle Scholar
  49. 49.
    Nakajima A, Tauchi T, Sumi M, Bishop WR, Ohyashiki K. Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells. Mol Cancer Ther. 2003;2:219–224.PubMedGoogle Scholar
  50. 50.
    Reuter CWM, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood. 2000;96:1655–1669.PubMedGoogle Scholar
  51. 51.
    Sebti SM, Hamilton AD. Farnesyltransferase and geranylgeranyl-transferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene. 2000;19:6584–6593.CrossRefPubMedGoogle Scholar
  52. 52.
    Liu M, Bryant MS, Chen J, et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res. 1998;58:4947–4956.PubMedGoogle Scholar
  53. 53.
    Ashar HR, James L, Gray K, et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem. 2000;275:30451–30457.CrossRefPubMedGoogle Scholar
  54. 54.
    Wang E, Casciano CN, Clement PR, Johnson WW. The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res. 2001;61:7525–7529.PubMedGoogle Scholar
  55. 55.
    Daley GQ. Towards combination target-directed chemotherapy for chronic myeloid leukemia: role for farnesyl transferase inhibitors. Semin Hematol. 2003;40:11–14.CrossRefPubMedGoogle Scholar
  56. 56.
    Cortes JE, Albitar M, Thomas D, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood. 2002;101:1692–1697.CrossRefPubMedGoogle Scholar
  57. 57.
    Raynaud FI, Orr RM, Goddard PM, et al. Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice. J Pharmacol Exp Ther. 1997;281:420–427.PubMedGoogle Scholar
  58. 58.
    Webb A, Cunningham D, Cotter F, et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet. 1997;349:1137–1141.CrossRefPubMedGoogle Scholar
  59. 59.
    Jansen B, Schlagbauer-Wadl H, Brown BD, et al. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med. 1998;4:232–234.CrossRefPubMedGoogle Scholar
  60. 60.
    Jansen B, Wacheck V, Heere-Ress E, et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet. 2000;356:1728–1733.CrossRefPubMedGoogle Scholar
  61. 61.
    Lopes de Menezes DE, Hudon N, Mclntosh N, Mayer LD. Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin. Clin Cancer Res. 2000;6:2891–2902.Google Scholar
  62. 62.
    Miayake H, Tolcher A, Gleave ME. Chemosentisization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. J Natl Cancer Inst. 2000;92:34–41.CrossRefPubMedGoogle Scholar
  63. 63.
    Wacheck V, Heere-Ress E, Halaschek-Wiener J, et al. Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model. J Mol Med. 2001;79:587–593.CrossRefPubMedGoogle Scholar
  64. 64.
    Chi KN, Gleave ME, Klasa R, et al. A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin Cancer Res. 2001;7:3920–3927.PubMedGoogle Scholar
  65. 65.
    Lopes de Menezes DE, Mayer LD. Phamacokinetics of Bcl-2 antisense oligonucleotide (G3139) combined with doxorubicin in SCID mice bearing human breast cancer solid tumor xenografts. Cancer Chemother Pharmacol. 2002;49:57–68.CrossRefGoogle Scholar
  66. 66.
    Rudin CM, Otterson GA, Mauer AM, et al. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol. 2002;13:539–545.CrossRefPubMedGoogle Scholar
  67. 67.
    Marcucci G, Byrd JC, Dai G, et al. Phase I and pharmacodynamic studies of G3139, a bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003;102:425–432.CrossRefGoogle Scholar
  68. 68.
    Tauchi T, Sumi M, Nakajima A, Sashida G, Shimamoto T, Ohyashiki K. BCL-2 antisense oligonucleotide Genasense is active against imatinib-resistant BCR-ABL-positive cells. Clin Cancer Res. 2003;9:4267–4273.PubMedGoogle Scholar
  69. 69.
    Iwama H, Ohyashiki K, Ohyashiki JH, et al. The relationship between telomere length and therapy-associated cytogenetic responses in patients with chronic myelogenous leukemia. Cancer. 1997;79:1552–1560.CrossRefPubMedGoogle Scholar
  70. 70.
    Ohyashiki K, Ohyashiki JH, Iwama H, Hayashi S, Shay JW, Toyama K. Telomerase activity and cytogenetic changes in chronic myeloid leukemia with disease progression. Leukemia. 1997;11:190–194.CrossRefPubMedGoogle Scholar
  71. 71.
    Ohyashiki JH, Sashida G, Tauchi T, Ohyashiki K. Telomeres and telomerase in hematologic neoplasia. Oncogene. 2002;21:680–687.CrossRefPubMedGoogle Scholar
  72. 72.
    Tauchi T, Nakajima A, Sashida G, et al. Inhibition of human telomerase enhances the effect of the tyrosine kinase inhibitor, imatinib, in BCR-ABL-positive leukemia cells. Clin Cancer Res. 2002;8:3341–3347.PubMedGoogle Scholar
  73. 73.
    Vigneri P, Wang JYJ. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001;7:228–234.CrossRefPubMedGoogle Scholar
  74. 74.
    Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–3860.CrossRefPubMedGoogle Scholar
  75. 75.
    Perkins CL, Fang G, Kim CN, et al. The role of Apaf-1, caspase-9, and Bid proteins in etoposideor paclitaxel-induced mitochondrial events during apoptosis. Cancer Res. 2000;60:1645–1653.PubMedGoogle Scholar
  76. 76.
    Perkins C, Kim CN, Fang G, Bhalla KN. Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpressed MDR, MRP, Bcl-2, or Bcl-xL. Blood. 2000;95:1014–1022.PubMedGoogle Scholar
  77. 77.
    Puccetti E, Guller S, Orleth A, et al. BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity. Cancer Res. 2000;60:3409–3413.PubMedGoogle Scholar
  78. 78.
    Porosnicu M, Nimmanapalli R, Nguyen D, Worthington E, Perkins C, Bhalla KN. Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells. Leukemia. 2001;15:772–778.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Nimmanapalli R, Bali P, O’Bryan E, et al. Arsenic trioxide inhibits translation of mRNA of bcr-abl, resulting in attenuation of Bcr-Abl levels and apoptosis of human leukemia cells. Cancer Res. 2003;63:7950–7958.PubMedGoogle Scholar
  80. 80.
    Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999;59:2615–2622.PubMedGoogle Scholar
  81. 81.
    Hamdane M, David-Cordonnier MH, D’Halluin JC. Activation of p65 NF-κB protein by p210BCR-ABL in a myeloid cell line (p210BCR-ABL activates p65 NF-κB). Oncogene. 1997;15:2267–2275.CrossRefPubMedGoogle Scholar
  82. 82.
    Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr. A requirement of NF-κB activation in Bcr-Abl-mediated transformation. Genes Dev. 1998;12:968–981.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Gatto SR, Scappini B, Verstovsek S, et al. In vitro effects of PS-341 alone and in combination with STI571 in BCR-ABL positive cell lines both sensitive and resistant to STI571 [abstract]. Blood. 2001;98:101a.Google Scholar
  84. 84.
    Zion M, Ben-Yehuda D, Avraham A, et al. Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia. Proc Natl Acad Sci USA. 1994;91:10722–10726.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Ben-Yehuda D, Krichevsky S, Rachmilewitz EA, et al. Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia. Blood. 1997;90:4918–4923.PubMedGoogle Scholar
  86. 86.
    Issa JP, Garcia-Manero G, Mannari R, et al. Minimal effective dose of hypomethylating agent decitabine in hematopoietic malignancies [abstract]. Blood. 2001;98:594a.CrossRefGoogle Scholar
  87. 87.
    Kantarjian HM, Talpaz M, Smith TL, et al. Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia. J Clin Oncol. 2000;18:3513–3512.CrossRefPubMedGoogle Scholar
  88. 88.
    Nimmanapalli R, Bhalla K. Novel targeted therapies for Bcr-Abl positive acute leukemias: beyond STI571. Oncogene. 2002;21:8584–8590.CrossRefPubMedGoogle Scholar
  89. 89.
    Nimmanapalli R, O’Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemia blasts. Cancer Res. 2001;61:1799–1804.PubMedGoogle Scholar
  90. 90.
    Nimmanapalli R, O’Bryan E, Huang M, et al. Molecular characterization and sensitivity of STI-571 (imatinib mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17-demethoxygel-danamycin. Cancer Res. 2002;62:5761–5769.PubMedGoogle Scholar
  91. 91.
    Blagosklonny MV. Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia. 2002;16:455–462.CrossRefPubMedGoogle Scholar
  92. 92.
    Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood. 2002;100:3041–3044.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Klejman A, Rushen L, Morrione A, Slupianek A, Skorski T. Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene. 2002;21:5868–5876.CrossRefPubMedGoogle Scholar
  94. 94.
    Walker EH, Pacold ME, Perisic O, et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell. 2000;6:909–919.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2004

Authors and Affiliations

  1. 1.First Department of Internal MedicineTokyo Medical UniversityTokyoJapan

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