Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Tyrosine Kinase Inhibitors in Ph+ Chronic Myeloid Leukemia Therapy: a Review

  • Shah, Krupa (Medicinal Chemistry & Pharmacogenomics, The Gujarat Cancer & Research Institute) ;
  • Parikh, Sonia (Dept. of Medical oncology, The Gujarat Cancer & Research Institute) ;
  • Rawal, Rakesh (Medicinal Chemistry & Pharmacogenomics, The Gujarat Cancer & Research Institute)
  • Published : 2016.07.01
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Abstract

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCR-ABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCR-ABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCR-ABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKI-insensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either pre-existing or induced due to therapy is still a challenge for the clinician. A proposed in-vitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling.

Keywords

References

  1. Ahmed N, Laverick L, Sammons J, et al (2001). Ajoene, a garlicderived natural compound, enhances chemotherapy-induced apoptosis in human myeloid leukaemia CD34-positive resistant cells. Anticancer Res, 21, 3519-23.
  2. Angelo C, Susan B, Michael D, et al (2013). What challenges remain in chronic myeloid leukemia research? Haematologica, 98, 1168-72. https://doi.org/10.3324/haematol.2013.090381
  3. Apperley JF, Cortes JE, Kim DW et al (2009). Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol, 27, 3472-9. https://doi.org/10.1200/JCO.2007.14.3339
  4. Biggs JC, Szer J, Crilley P, et al (1992). Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2. Blood, 80, 1352-7.
  5. Bing C, Duncan M, Jorge C, et al (2010). The elusive CML stem cell: does it matter and how do we eliminate it? Semin Hematol, 47, 362-370. https://doi.org/10.1053/j.seminhematol.2010.06.006
  6. Bonifacio M, Rigo A, Guardalben E, et al (2012). a-bisabolol is an effective proapoptotic agent against BCR-ABL+ Cells in synergism with imatinib and nilotinib. Plos One, 7, 46674. https://doi.org/10.1371/journal.pone.0046674
  7. Branford S, Rudzki Z, Walsh S et al (2003). Detection of BCRABL 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, 102, 276 -283. https://doi.org/10.1182/blood-2002-09-2896
  8. Buchdunger E, Cioffi CL, Law N (2000). 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, 295, 139-45.
  9. Calabretta B. and Perrotti D. (2004).The biology of CML blast crisis. Blood, 103, 4010-22. https://doi.org/10.1182/blood-2003-12-4111
  10. Can G, Cakir Z, Kartal M, et al (2012). Apoptotic effects of resveratrol, a grape polyphenol, on imatinib-sensitive and resistant K562 chronic myeloid leukemia cells. Anticancer Res, 32, 2673-8.
  11. Chan WW, Wise SC, Kaufman MD, et al (2011). Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell, 19, 556-68. https://doi.org/10.1016/j.ccr.2011.03.003
  12. Chandramohan R, Bharat D, Aparna A (2012). Anti-leukemic effects of gallic acid on human leukemia K562 cells: downregulation of COX-2, inhibition of BCR/ABL kinase and $NF-{\kappa}B$ inactivation. Toxicol In Vitro, 26, 396-405. https://doi.org/10.1016/j.tiv.2011.12.018
  13. Cheetham GM, Charlton PA, Golec JM, et al (2007). Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680. Cancer Lett, 251, 323-9. https://doi.org/10.1016/j.canlet.2006.12.004
  14. Chen Y, Peng C, Li D, et al (2010). Molecular and cellular bases of chronic myeloid leukemia. Protein Cell, 1, 124-32. https://doi.org/10.1007/s13238-010-0016-z
  15. Cohen MH, Williams G, Johnson JR, et al (2002). Approval summary for matinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res, 8, 935-42
  16. Colavita I, Esposito N, Martinelli R, et al (2010). Gaining insights into the Bcr-Abl activity-independent mechanisms of resistance to imatinib mesylate in KCL22 cells: a comparative proteomic approach. Biochim Biophys Acta, 1804, 1974-87. https://doi.org/10.1016/j.bbapap.2010.04.009
  17. compounds to leukemia cells in vitro. Cancer Therapy, 6, 733-740.
  18. Copland M, Hamilton A, Eirick LJ, et al (2006). Dasatinib (BMS-354825) targets an earlier progenitor population than Imatinib in primary CML but does not eliminate the quiescent fraction. Blood, 107, 4532-39. https://doi.org/10.1182/blood-2005-07-2947
  19. Cortes J (2004). Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am, 18, 569-84. https://doi.org/10.1016/j.hoc.2004.03.011
  20. Cortes J, Kim DW, Raffoux E et al (2008). Efficacy and safety of dasatinib in imatinib-resistant or - intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 22, 2176-83. https://doi.org/10.1038/leu.2008.221
  21. Cortes JE, Kantarjian HM, Brummendorf TH, et al (2011). Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive CML patients with resistance or intolerance to imatinib. Blood, 118, 4567-8 https://doi.org/10.1182/blood-2011-05-355594
  22. Cortes JE, Kim DW, Pinilla-Ibarz J, et al (2012). PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol, 30, 6503.
  23. Cortes JE, Kim DW, Pinilla-Ibarz J, et al (2013). A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med, 369, 1783-96. https://doi.org/10.1056/NEJMoa1306494
  24. Cortes JE, Kim DW, Kantarjian HM (2012) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol, 1, 3486-92.
  25. Deininger M, Buchdunger E, Druker BJ (2005). The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood, 105, 2640-53. https://doi.org/10.1182/blood-2004-08-3097
  26. Deininger MW, Goldman JM, Melo JV (2000). The molecular biology of chronic myeloid leukemia. Blood, 96, 3343-56.
  27. Deininger W, Goldman M, Lydon N. et al (1997). The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood, 90, 3691-8.
  28. Desai UN, Shah KP, Mirza SH (2015). Enhancement of the cytotoxic effects of cytarabine in synergism with hesperidine and silibinin in acute myeloid leukemia: An in-vitro approach. J Cancer Res Ther, 11, 352-7. https://doi.org/10.4103/0973-1482.157330
  29. Donato NJ, Wu JY, Stapley J et al (2003). BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood, 101, 690-8. https://doi.org/10.1182/blood.V101.2.690
  30. Druker J, Tamura S, Buchdunger E, et al (1996). Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med, 2, 561-6. https://doi.org/10.1038/nm0596-561
  31. Edurne San Jose-Eneriz et al (2009). MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations. Molecular Cancer, 8, 69 https://doi.org/10.1186/1476-4598-8-69
  32. Faderl S, Talpaz M, Estrov Z et al (1999). Chronic myelogenous leukemia: biology and therapy. Ann Intern Med, 131, 207-19. https://doi.org/10.7326/0003-4819-131-3-199908030-00008
  33. Fiskus W, Pranpat M, Bali P, et al (2006). Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl expressing human leukemia cells. Blood, 108, 645-52. https://doi.org/10.1182/blood-2005-11-4639
  34. Flamant S, Ritchie W, Guilhot J, et al (2010). Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia. Haematologica, 95, 1325-33. https://doi.org/10.3324/haematol.2009.020636
  35. Flamant S, Ritchie W, Guilhot J, et al (2010). Micro-RNA response to Imatinib mesylate in patients with chronic myeloid leukemia. Haematologica, 95, 1325-33. https://doi.org/10.3324/haematol.2009.020636
  36. Fontana S, Alessandro R, Barranca M, et al. (2007) Comparative proteome profiling and functional analysis of chronic myelogenous leukemia cell lines. J Proteosome Res, 6, 4330-42. https://doi.org/10.1021/pr0704128
  37. Galimberti S., Cervetti G., Guerrini F, et al (2005). Quantitative molecular monitoring of BCR-ABL and MDR1 transcripts in patients with chronic myeloid leukaemia during Imatinib treatment. Cancer Genet Cytogenet, 162, 57-62 https://doi.org/10.1016/j.cancergencyto.2005.01.015
  38. Galton DA (1953). Myleran in chronic myeloid leukaemia; results of treatment. Lancet, 264, 208-13.
  39. Gambacorti C, Cortes J, Kim D, et al (2014). Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol, 89, 947-53. https://doi.org/10.1002/ajh.23788
  40. Gambacorti CB, Rossi F, Verga M, et al (2002). Differences between in vivo and in vitro sensitivity to Imatinib of Bcr/Abl+ cells obtained from leukemic patients. Blood Cells Mol Dis, 28, 361-72. https://doi.org/10.1006/bcmd.2002.0526
  41. Gambacorti-Passerini C, Barni R, le Coutre P et al (2000). 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, 92, 1641-50. https://doi.org/10.1093/jnci/92.20.1641
  42. Gambacorti-PC, Brummendorf T, Kantarjian H, et al (2007). Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib. J Clin Oncol, 25, 7006.
  43. Geylani C, Zeynep C, Melis K (2012). Apoptotic effects of resveratrol, a grape polyphenol, on imatinib-sensitive and resistant K562 chronic myeloid leukemia cells. Anticancer Res, 32, 72673-2678.
  44. Giles FJ, Larson RA, Kantarjian HM, et al (2008). Nilotinib in patients (pts) with philadelphia chromosome-positive (ph+) chronic myelogenous leukemia in Blast Crisis (CML-BC) who are resistant or intolerant to imatinib. J Clin Oncol, 26, 701.
  45. Gishizky ML, Johnson-White J, Witte ON (1993). Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice. Proc Natl Acad Sci U S A, 90, 3755-3759. https://doi.org/10.1073/pnas.90.8.3755
  46. Goldman JM (2010). Chronic myeloid leukemia: a historical perspective. Seminars Hematol, 47, 302-11. https://doi.org/10.1053/j.seminhematol.2010.07.001
  47. Gorre ME, Ellwood K, Chiosis G (2002). BCR-ABL point mutants isolated from patients with imatinib mesylateresistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood, 100, 3041-4. https://doi.org/10.1182/blood-2002-05-1361
  48. Gorre ME, Mohammed M, Ellwood K, et al (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science, 293, 876-80. https://doi.org/10.1126/science.1062538
  49. Hehlmann R, Hochhaus A, Baccarani M, et al (2007). European leukemia net. chronic myeloid leukaemia. Lancet, 370, 342-50. https://doi.org/10.1016/S0140-6736(07)61165-9
  50. Heinrich C, Griffith J., Druker J.et al (2000). Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood, 96, 925-32.
  51. Hershkovitz O, Granot G, Ovcharenko A, et al. (2012) Downregulation of mir-31, mir-155, and mir-564 in chronic myeloid leukemia cells. PLoS ONE, 7, 35501. https://doi.org/10.1371/journal.pone.0035501
  52. Hochhaus A, Baccarani M, Deininger M et al (2008). Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia, 22, 1200-6. https://doi.org/10.1038/leu.2008.84
  53. Hochhaus A, Kreil S, Corbin AS et al (2002). Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia, 16, 2190-6. https://doi.org/10.1038/sj.leu.2402741
  54. Hu Y, Swerdlow S, DuffyTMet al (2006). Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph_ leukemia in mice. Proc Natl Acad Sci U S A, 103, 16870-5. https://doi.org/10.1073/pnas.0606509103
  55. Hughes TP, Hochhaus A, Branford S, et al (2010). Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood, 116, 3758-65. https://doi.org/10.1182/blood-2010-03-273979
  56. Illmer T, Schaich M, Platzbecker U et al (2004). P-glycoproteinmediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia, 18, 401-8. https://doi.org/10.1038/sj.leu.2403257
  57. Jamshid K, Todd K, Philippe S, et al (2013). BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood, 121, 489-98. https://doi.org/10.1182/blood-2012-05-431379
  58. Jelinek J, Gharibyan V, Estecio, et al. (2011) Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia. PLoS ONE, 6, 22110. https://doi.org/10.1371/journal.pone.0022110
  59. Jiang X, Delaney A, Eaves A, et al (2005) Leukemic stem cells from CML patients have uniquely elevated BCR-ABL activity explaining their selective resistance to Imatinib mesylate but also contain subpopulations with kinase mutations. Exp Hematol, 33, 50.
  60. Jorgensen HG, Elliott MA, Allan EK, et al (2002). Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571. Blood, 99, 713-15. https://doi.org/10.1182/blood.V99.2.713
  61. Kantarjian H, Cortes J, Kim DW, et al (2009). Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median followup. Blood, 113, 6322-9. https://doi.org/10.1182/blood-2008-11-186817
  62. Kantarjian H, Giles F, Wunderle L, et al (2006). Nilotinib in imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med, 354, 2542-1. https://doi.org/10.1056/NEJMoa055104
  63. Kantarjian H, Shah NP, Hochhaus A, et al (2010). Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med, 362, 2260-70. https://doi.org/10.1056/NEJMoa1002315
  64. Kantarjian H, Sawyers C, Hochhaus A, et al (2002). Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med, 346, 645-52. https://doi.org/10.1056/NEJMoa011573
  65. Kantarjian HM, Giles FJ, Bhalla KN, et al (2011). Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood, 117, 1141-5. https://doi.org/10.1182/blood-2010-03-277152
  66. Kantarjian HM, O'Brien S, Cortes JE, et al (2003). Complete cytogenetic and molecular responses to interferon-alphabased therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer, 97, 1033-41. https://doi.org/10.1002/cncr.11223
  67. Kantarjian HM, Talpaz M, Giles F et al (2006). New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med, 145, 913-23. https://doi.org/10.7326/0003-4819-145-12-200612190-00008
  68. Kastner R, Zopf A, Preuner S et.al (2014). Rapid identification of compound mutations in patients with Philadelphia-positive leukaemias by long-range next generation sequencing. EurJ Cancer, 50, 793-800. https://doi.org/10.1016/j.ejca.2013.11.030
  69. Katerina P (2011). Expression patterns of microRNAs associated with CML phases and their disease related targets. Mol Cancer, 10, 41. https://doi.org/10.1186/1476-4598-10-41
  70. Katerina P, Jitka K, Tomas Stopka (2013). Role of Epigenetics in Chronic Myeloid Leukemia. Curr Hematol Malig Rep 8, 28-36. https://doi.org/10.1007/s11899-012-0152-z
  71. La Rosee P, Shen L, Stoff EP, et al (2003). No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of Imatinib mesylate (Gleevec/Glivec). Hematol J, 4, 413-19. https://doi.org/10.1038/sj.thj.6200297
  72. le Coutre P, Kreuzer KA, Na IK et al (2002). Determination of alpha-1 acid glycoprotein in patients with Ph_ chronic myeloid leukemia during the first 13 weeks of therapy with STI571. Blood Cells Mol Dis, 28, 75-85. https://doi.org/10.1006/bcmd.2002.0493
  73. le Coutre P, Tassi E, Varella-Garcia M, et al (2000). Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood, 95, 1758-66.
  74. Lombardo LJ, Lee FY, Chen P, et al (2004). Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem, 47, 6658-61. https://doi.org/10.1021/jm049486a
  75. Lubbert M (2000). DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol, 249, 135-64.
  76. Lucas DM, Still PC, Perez LB, et al (2010) Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma. Curr Drug Targets, 11, 812-22. https://doi.org/10.2174/138945010791320809
  77. Mahon FX, Deininger MW, Schultheis B, et al (2000). Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood, 96, 1070-9.
  78. Marina B, Harvey L (2011). MicroRNAs: the primary cause or a determinant of progression in leukemia? Expert Rev Hematol, 4, 121-3. https://doi.org/10.1586/ehm.11.6
  79. Markus D, Maciej S (2008). Cytotoxic effects of a combination of three natural
  80. Mello JV, Chuah C (2007). Resistance to imatinib mesylate in chronic myeloid
  81. Meng Y, Li Y, Li J, et al (2007). (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leuk lymphoma, 48, 2204-12. https://doi.org/10.1080/10428190701583991
  82. Nimmanapalli R, Fuino L, Stobaugh C, et al (2003). Co treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood, 101, 3236-9. https://doi.org/10.1182/blood-2002-08-2675
  83. Nimmanapalli R, O'Bryan E, Bhalla K (2001). Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr- Abl-positive human leukemic blasts. Cancer Res, 61, 1799-804.
  84. Nowell PC & Hungerford DA (1960). A minute chromosome in human chronic granulocytic leukemia. Science, 142, 1497.
  85. Nowell PC and Hungerford DA. (1960).Chromosome studies on normal and leukemic human leukocytes. J National Cancer Institute, 25, 85-109,
  86. O'Brien SG, F. Guilhot, RA. Larsonet, et al (2003). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. New England J Med, 348, 994-1004. https://doi.org/10.1056/NEJMoa022457
  87. O'Brien SG, Guilhot F, Larson RA, et al (2003). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med, 348, 994-1004 https://doi.org/10.1056/NEJMoa022457
  88. O'Hare T, Shakespeare WC, Zhu X, et al (2009). AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and and overcomes mutation-based resistance. Cancer Cell, 16, 401-12. https://doi.org/10.1016/j.ccr.2009.09.028
  89. O'Hare T, Walters DK, Stoffregen EP, et al (2005). In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res, 65, 4500-5. https://doi.org/10.1158/0008-5472.CAN-05-0259
  90. Okuda K, Weisberg E, Gilliland D. G, et al (2001). ARG tyrosine kinase activity is inhibited by STI571. Blood, 97, 2440-8. https://doi.org/10.1182/blood.V97.8.2440
  91. Pan L, Chai HB, Kinghorn A (2012).Discovery of new anticancer agents from higher plants. Front Biosci, 1, 142-156.
  92. Pizzatti L, Sa LA, de Souza JM, et al (2006). Altered protein profile in chronic myeloid leukemia chronic phase identified by a comparative proteomic study. Biochim Biophys Acta. 1764, 929-42. https://doi.org/10.1016/j.bbapap.2006.02.004
  93. Puissant A, Grosso S, Jacquel A, (2008). Imatinib mesylateresistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol. FASEB J, 22, 1894-904. https://doi.org/10.1096/fj.07-101394
  94. Puttini M, Coluccia AM, Boschelli F, et al (2006). In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res, 66, 11314-22. https://doi.org/10.1158/0008-5472.CAN-06-1199
  95. Quintas CA, Cortes J (2009). Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood, 113, 1619-30. https://doi.org/10.1182/blood-2008-03-144790
  96. Redaelli S, Piazza R, Rostagno R, et al (2009). Activity of bosutinib, dasatinib, and nilotinib against 18 imatinibresistant BCR/ABL mutants. J Clin Oncol, 27, 469-71. https://doi.org/10.1200/JCO.2008.19.8853
  97. Rohrabacher M. and Hasford J. (2009). Epidemiology of chronic myeloid leukaemia (CML). Best Practice Res, 22, 295-302.
  98. Rowley JD (1973). A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature, 243, 290-3. https://doi.org/10.1038/243290a0
  99. Saglio G, Hochhaus A, Goh YT, et al (2010). Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer, 116, 3852-61. https://doi.org/10.1002/cncr.25123
  100. Saglio G, Kim DW, Issaragrisil S, et al (2010). Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med, 362, 2251-9. https://doi.org/10.1056/NEJMoa0912614
  101. SanJose E, Roman J, Jimenez A et al (2009). MicroRNA expression profiling in Imatinib-resistant chronic myeloid leukemia patients without clinically significant ABL1-mutations. Molecular Cancer, 8, 69. https://doi.org/10.1186/1476-4598-8-69
  102. Sawyers CL (1999). Chronic myeloid leukemia. N Engl J Med, 340, 1330-40. https://doi.org/10.1056/NEJM199904293401706
  103. Shah NP, Kantarjian HM, Kim DW, et al (2008). Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic phase chronic myeloid leukemia. J Clin Oncol, 26, 3204-12. https://doi.org/10.1200/JCO.2007.14.9260
  104. Shah NP, Kim DW, Kantarjian H, et al (2010). Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica, 95,232-240. https://doi.org/10.3324/haematol.2009.011452
  105. Shah NP, Tran C, Lee FY, et al (2004). Overriding imatinib resistance with a novel ABL kinase inhibitor. Science, 305, 399-401. https://doi.org/10.1126/science.1099480
  106. Soverini S, Colarossi S, Gnani A, et al (2006). Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of philadelphia positive patients: By the GIMEMA working party on chronic myeloid leukemia. Clin Cancer Res, 12, 7374 -9. https://doi.org/10.1158/1078-0432.CCR-06-1516
  107. Soverini S, Martinelli G, Rosti G et al (2005). ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: A study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol, 23, 4100-9. https://doi.org/10.1200/JCO.2005.05.531
  108. Sun B, Jiang G, Zaydan MA et al (2001). ABL1 promoter methylation can exist independently of BCR-ABL transcription in chronic myeloid leukemia hematopoietic progenitors. Cancer Res, 15, 6931-7.
  109. Talpaz M, Shah NP, Kantarjian H et al (2006). Dasatinib in imatinib-resistant Philadelphia chromosome positive leukemias. N Engl J Med, 354, 2531-41. https://doi.org/10.1056/NEJMoa055229
  110. Talpaz M, Silver T, Druker J et al (2002). Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood, 99, 1928-37. https://doi.org/10.1182/blood.V99.6.1928
  111. Tokarski JS, Newitt JA, Chang CY, et al (2006). The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinibresistant ABL mutants. Cancer Res. 66, 5790-7. https://doi.org/10.1158/0008-5472.CAN-05-4187
  112. Visani G, Russo D, Ottaviani E, et al (1997). Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on 'in vitro' growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors. Leukemia, 11, 624-8. https://doi.org/10.1038/sj.leu.2400608
  113. Weisberg E, Manley PW, Breitenstein W, et al (2005). Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell, 7, 129-141. https://doi.org/10.1016/j.ccr.2005.01.007
  114. White DL, Saunders VA, Dang P et al (2010) OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia, 24, 1962-5. https://doi.org/10.1038/leu.2010.188
  115. White DL, Saunders VA, Dang P, et al (2006). OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood, 108, 697-704. https://doi.org/10.1182/blood-2005-11-4687
  116. White DL, Saunders VA, Dang P, et al (2008). CML patients with low OCT-1 activity achieves better molecular responses on high dose Imatinib than on standard dose. Blood, 112, 3187.
  117. Wu LX, Wu Y, Chen RJ, et al (2014). Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro. Acta Pharmacol Sin, 35, 401-9. https://doi.org/10.1038/aps.2013.180
  118. Yang M, Yan Li, Jing Li, et al (2007). (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leukemia Lymphoma, 48, 2204-12. https://doi.org/10.1080/10428190701583991
  119. Yu C, Rahmani M, Almenara J, et al (2003). Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res, 63, 2118-26.
  120. Yu C, Rahmani M, Conrad D, et al (2003). The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood, 102, 3765-74. https://doi.org/10.1182/blood-2003-03-0737
  121. Zhang H, Trachootham D, Lu W, et al (2008). Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia, 22, 1191-9. https://doi.org/10.1038/leu.2008.74
  122. Zhang J, Adrian J, Jahnke W, et al (2010). Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 463, 501-6. https://doi.org/10.1038/nature08675
  123. Zhu XS, Lin ZY, DU J, et al (2014). Clinical significance of BCR-ABL fusion gene subtypes in chronic myelogenous and acute lymphoblsticleukemias. Asian Pac J Cancer Prev, 15, 4773-80. https://doi.org/10.7314/APJCP.2014.15.12.4773