EGFR

Роль селективности ингибиторов тирозинкиназ в развитии побочных эффектов при терапии хронического миелолейкоза

ОБЗОРЫ , , , , , , , , , , , , , ,

А.А. Зейфман1,2, Е.Ю. Челышева3, А.Г. Туркина3, Г.Г. Чилов1,2

1 ФГБУ «Институт органической химии им. Н.Д. Зелинского РАН», Москва, Российская Федерация

2 ООО «Фьюжн Фарма», Москва, Российская Федерация

3 ФГБУ «Гематологический научный центр» МЗ РФ, Москва, Российская Федерация

РЕФЕРАТ

В обзоре рассмотрен вопрос о связи селективности ингибиторов Bcr-Abl-киназ со спектром нежелательных побочных эффектов у больных хроническим миелолейкозом при проведении терапии. Суммированы данные по структуре и естественным биохимическим функциям наиболее хорошо изученных побочных мишеней ингибиторов Bcr-Abl-киназ: BRAF, FMS, EGFR, PDGFR, PYK2, TIE2, VEGFR1/2/3, а также оценена возможная связь их нецелевого ингибирования и нежелательных побочных эффектов ингибиторов тирозинкиназ.

Ключевые слова: хронический миелолейкоз, ингибиторы тирозинкиназ, селективность, иматиниб, нилотиниб, дазатиниб, понатиниб, PF-114, BRAF, FMS, EGFR, PDGFR, PYK2, TIE2, VEGFR1/2/3.

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ЛИТЕРАТУРА

  1. Chartier M., Chenard T., Barker J. et al. Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. Peer J. 2013; 1: e126.
  2. Soverini S., Hochhaus A., Nicolini F.E. et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011; 118(5): 1208–15.
  3. Куцев С.И., Вельченко М.В. Значение анализа мутаций гена BCR-ABL в оптимизации таргетной терапии хронического миелолейкоза. Клин. онкогематол. 2008; 1(3): 190–9. [Kutsev S.I., Velchenko M.V. Significance of analysis of BCR-ABL gene mutations in optimization of target therapy for chronic myeloid leukemia. Klin. onkogematol. 2008; 1(3): 190–9. (In Russ.)].
  4. Челышева Е.Ю., Шухов О.А., Лазарева О.В. и др. Мутации гена BCR-ABL при хроническом миелолейкозе. Клин. онкогематол. 2012; 5(1): 13–21. [Chelysheva Ye.Yu., Shukhov O.A., Lazareva O.V. et al. BCR-ABL gene mutations in chronic myeloid leukemia. Klin. onkogematol. 2012; 5(1): 13–21. (In Russ.)].
  5. Lombardo L.J., Lee F.Y., Chen P. et al. Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem 2004; 47(27): 6658–61.
  6. Weisberg E., Manley P.W., Breitenstein W. et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7(2): 129–41.
  7. Golas J.M., Arndt K., Etienne C. et al. SKI-606, a 4-anilino-3-quinoline carbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res 2003; 63(2): 375–81.
  8. O’Hare T., Shakespeare W.C., Zhu X. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16(5): 401–12.
  9. Mian A.A., Badura S., Rafiei A. et al. PF-114, a novel selective pan-Bcr/ Abl inhibitor for Philadelphia chromosome positive (Ph+) leukemia, effectively targets T315I and the other resistance mutants. European Hematologic Association, Stockholm, Sweden, June 13–16, 2013: S1177.
  10. Anastassiadis T., Deacon S.W., Devarajan K. et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol. 2011; 29(11): 1039–45.
  11. Saglio G., Kim D.W., Issaragrisil S. et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 2010; 362(24): 2251–9.
  12. Kantarjian H., Shah N.P., Hochhaus A. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 2010; 362(24): 2260–70.
  13. Davis M.I., Hunt J.P., Herrgard S. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 2011; 29(11): 1046–51.
  14. Martins D.H., Wagner S.C., Dos Santos T.V. et al. Monitoring imatinib plasma concentrations in chronic myeloid leukemia. Rev. Bras. Hematol. Hemother. 2011; 33(4): 302–6.
  15. Demetri G.D., Lo Russo P., MacPherson I.R. et al. Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin. Cancer Res. 2009; 15(19): 6232–40.
  16. Manley P.W., Drueckes P., Fendrich G. et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochem. Biophys. Acta 2010; 1804(3): 445–53.
  17. Bradeen H.A., Eide C.A., O’Hare T. et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 2006; 108(7): 2332–8.
  18. Remsing Rix L.L., Rix U., Colinge J. et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia 2009; 23(3): 477–85.
  19. Cortes J.E., Kantarjian H.M., Brummendorf T.H. et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011; 118(17): 4567–76.
  20. Schrock A.B., Gozgit J.M., Rivera V. The pan-BCR-ABL inhibitor ponatinib inhibits viability of gatekeeper mutant BCR-ABLT315I cells with greater potency than a nilotinib/MEK inhibitor combination. Clin. Cancer Res. 2012; 18: Abstract B15.
  21. Sonnichsen D., Dorer D.J., Cortes J. et al. Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies. Cancer Chemother. Pharmacol. 2013; 71(6): 1599–607.
  22. Chan W.W., Wise S.C., Kaufman M.D. et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 2011; 19(4): 556–68.
  23. Fiskus W., Smith C.C., Smith J. et al. Activity of Allosteric, Switch-Pocket, ABL/FLT3 Kinase Inhibitor DCC2036 Against Cultured and Primary AML Progenitors with FLT-ITD or FLT3 Kinase Domain Mutations. 53rd ASH Annual Meeting and Exposition, 2011.
  24. Fancelli D., Moll J., Varasi M. et al. 1,4,5,6-tetrahydropyrrolo[3,4-c] pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J. Med. Chem. 2006; 49(24): 7247–51.
  25. Steeghs N., Eskens F.A., Gelderblom H. et al. Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J. Clin. Oncol. 2009; 27(30): 5094–101.
  26. Ruthardt M. PF-114, a novel selective PAN BCR/ABL inhibitor for Philadelphia chromosome-positive (Ph+) leukemia, effectively targets T315I and other resistance mutant. 15th International Conference on Chronic Myeloid Leukemia: Biology and Therapy, 2013.
  27. Uniprot for BRAF. Available from: http://www.uniprot.org/uniprot/P15056.
  28. Davies H., Bignell G.R., Cox C. et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417(6892): 949–54.
  29. Pratilas C.A., Xing F., Solit D.B. Targeting oncogenic BRAF in human cancer. Curr. Top Microbiol. Immunol. 2012; 355: 83–98.
  30. Roskoski R.Jr. RAF protein-serine/threonine kinases: structure and regulation. Biochem. Biophys. Res. Commun. 2010; 399(3): 313–7.
  31. Chang F., Steelman L.S., Lee J.T. et al. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003; 17(7): 1263–93.
  32. Wellbrock C., Karasarides M., Marais R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 2004; 5(11): 875–85.
  33. Freeman A.K., Ritt D.A., Morrison D.K. Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol. Cell 2013; 49(4): 751–8.
  34. Sabbatino F., Wang Y., Wang X. et al. Emerging BRAF inhibitors for melanoma. Exp. Opin. Emerg. Drugs 2013; 18(4): 431–43.
  35. Boussemart L., Routier E., Mateus C. et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann. Oncol. 2013; 24(6): 1691–7.
  36. Huang V., Hepper D., Anadkat M. et al. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch. Dermatol. 2012; 148(5): 628–33.
  37. Hey F., Pritchard C. A new mode of RAF autoregulation: a further complication in the inhibitor paradox. Cancer Cell 2013; 23(5): 561–3.
  38. FDA, Risk Assessment And Risk Mitigation Review(S) for Iclusig (ponatinib), 2012.
  39. Drucker A.M., Wu S., Busam K.J. et al. Rash with the multitargeted kinase inhibitors nilotinib and dasatinib: meta-analysis and clinical characterization. Eur. J. Haematol. 2013; 90(2): 142–50.
  40. Uniprot for c-FMS. Available from: http://www.uniprot.org/uniprot/P07333.
  41. Bourette R.P., Rohrschneider L.R. Early events in M-CSF receptor signaling. Growth Factors 2000; 17(3): 155–66.
  42. Zaidi M. Skeletal remodeling in health and disease. Nat. Med. 2007; 13(7): 791–801.
  43. Kimura K., Kitaura H., Fujii T. et al. An anti-c-Fms antibody inhibits osteoclastogenesis in a mouse periodontitis model. Oral Dis. 2013 [Epub ahead of print].
  44. Nurmio M., Joki H., Kallio J. et al. Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats. Toxicol. Appl. Pharmacol. 2011; 254(3): 267–79.
  45. Hamilton J.A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 2008; 8(7): 533–44.
  46. Paniagua R.T., Chang A., Mariano M.M. et al. c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. Arthritis Res. Ther. 2010; 12(1): R32.
  47. Lim A.K., Ma F.Y., Nikolic-Paterson D.J. et al. Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice. Diabetologia 2009; 52(8): 1669–79.
  48. Baay M., Brouwer A., Pauwels P. et al. Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy. Clin. Dev. Immunol. 2011; 2011: 12.
  49. Ovadia S., Insogna K., Yao G.Q. The cell-surface isoform of colony stimulating factor 1 (CSF1) restores but does not completely normalize fecundity in CSF1-deficient mice. Biol. Reprod. 2006; 74(2): 331–6.
  50. Salmassi A., Mettler L., Jonat W. et al. Circulating level of macrophage colony-stimulating factor can be predictive for human in vitro fertilization outcome. F rtil. Steril. 2010; 93(1): 116–23.
  51. Narayanan K.R., Bansal D., Walia R. et al. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatr. Blood Cancer 2013; 60(7): 1148–53.
  52. Iclusig (ponatinib) prescribing information. 53. Bosulif (Bosutinib) prescribing information.
  53. Uniprot for EGFR. Available from: http://www.uniprot.org/uniprot/P00533.
  54. Hynes N.E., Lane H.A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 2005; 5(5): 341–54.
  55. Reuter C.W., Morgan M.A., Eckardt A. Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br. J. Cancer 2007; 96(3): 408–16.
  56. Lenz H.J. Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncology (Williston Park) 2006; 20(5 Suppl. 2): 5–13.
  57. Perez-Soler R. Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? Oncology (Williston Park) 2003; 17(11 Suppl. 12): 23–8.
  58. Murillas R., Larcher F., Conti C.J. et al. Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J. 1995; 14(21): 5216–23.
  59. Yano S., Kondo K., Yamaguchi M. et al. Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Res. 2003; 23(5A): 3639–50.
  60. Lee Y., Shim H.S., Park M.S. et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with advanced squamous cell lung carcinoma. Clin. Cancer Res. 2012; 18(6): 1760–8.
  61. Perez-Soler R., Delord J.P., Halpern A. et al. HER1/EGFR inhibitorassociated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005; 10(5): 345–56.
  62. Takeda K., Hida T., Sato T. et al. Randomized phase III trial of platinumdoublet chemotherapy followed by gefitinib compared with continued platinumdoublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). J. Clin. Oncol. 2010; 28(5): 753–60.
  63. Erlotinib(Iressa) prescribing information.
  64. Sprycel (dasatinib) prescribing information.
  65. Uniprot for PDGFRA. Available from: http://www.uniprot.org/uniprot/ P16234.
  66. Uniprot for PDGFRB. Available from: http://www.uniprot.org/uniprot/ P09619.
  67. Hoch R.V., Soriano P. Roles of PDGF in animal development. Development 2003; 130(20): 4769–84.
  68. Shim A.H., Liu H., Focia P.J. et al. Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proc. Natl. Acad. Sci. U S A 2010; 107(25): 11307–12.
  69. Andrae J., Gallini R., Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008; 22(10): 1276–312.
  70. Eckhardt S.G., Rizzo J., Sweeney K.R. et al. Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors. J. Clin. Oncol. 1999; 17(4): 1095–104.
  71. Kuenen B.C., Giaccone G., Ruijter R. et al. Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies. Clin. Cancer Res. 2005; 11(17): 6240–6.
  72. Jayson G.C., Parker G.J., Mullamitha S. et al. Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab’, leads to fluid accumulation and is associated with increased tumor vascularized volume. J. Clin. Oncol. 2005; 23(5): 973–81.
  73. Kelly K., Swords R., Mahalingam D. et al. Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors. Target Oncol. 2009; 4(2): 99–105.
  74. Berman E., Nicolaides M., Maki R.G. et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N. Engl. J. Med. 2006; 354(19): 2006–13.
  75. O’Sullivan S., Naot D., Callon K. et al. Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms. J. Bone Miner. Res. 2007; 22(11): 1679–89.
  76. Tasigna (nilotinib) prescribing information.
  77. Uniprot for PYK2. Available from: http://www.uniprot.org/uniprot/Q14289.
  78. Lipinski C.A., Loftus J.C. Targeting Pyk2 for therapeutic intervention. Exp. Opin. Ther. Targets 2010; 14(1): 95–108.
  79. Raja S., Avraham S., Avraham H. Tyrosine phosphorylation of the novel protein-tyrosine kinase RAFTK during an early phase of platelet activation by an integrin glycoprotein IIb-IIIa-independent mechanism. J. Biol. Chem. 1997; 272(16): 10941–7.
  80. Ohmori T., Yatomi Y., Asazuma N. et al. Involvement of proline-rich tyrosine kinase 2 in platelet activation: tyrosine phosphorylation mostly dependent on alphaIIb beta3 integrin and protein kinase C, translocation to the cytoskeleton and association with Shc through Grb2. Biochem. J. 2000; 347(Pt. 2): 561–9.
  81. Canobbio I., Cipolla L., Consonni A. et al. Impaired thrombin-induced platelet activation and thrombus formation in mice lacking the Ca(2+)-dependent tyrosine kinase Pyk2. Blood 2013; 121(4): 648–57.
  82. Okigaki M., Davis C., Falasca M. et al. Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc. Natl. Acad. Sci. U S A 2003; 100(19): 10740–5.
  83. Kamen L.A., Schlessinger J., Lowell C.A. Pyk2 is required for neutrophil degranulation and host defense responses to bacterial infection. J. Immunol. 2011; 186(3): 1656–65.
  84. Gil-Henn H., Destaing O., Sims N.A. et al. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice. J. Cell Biol. 2007; 178(6): 1053–64.
  85. Buckbinder L., Crawford D.T., Qi H. et al. Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc. Natl. Acad. Sci. U S A 2007; 104(25): 10619–24.
  86. Eleniste P.P., Bruzzaniti A. Focal adhesion kinases in adhesion structures and disease. J. Signal Transduct. 2012; 2012: 296450.
  87. Uniprot for Angiopoietin-1 receptor. Available from: http://www.uniprot. org/uniprot/Q02763.
  88. Barton W.A., Tzvetkova-Robev D., Miranda E.P. et al. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat. Struct. Mol. Biol. 2006; 13(6): 524–32.
  89. Huang H., Bhat A., Woodnutt G. et al. Targeting the ANGPT-TIE2 pathway in malignancy. Nat. Rev. Cancer 2010; 10(8): 575–85.
  90. Sato T.N., Tozawa Y., Deutsch U. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995; 376(6535): 70–4.
  91. Jones N., Voskas D., Master Z. et al. Rescue of the early vascular defects in Tek/Tie2 null mice reveals an essential survival function. EMBO Rep. 2001; 2(5): 438–45.
  92. Peters K.G., Kontos C.D., Lin P.C. et al. Functional significance of Tie2 signaling in the adult vasculature. Rec. Prog. Horm. Res. 2004; 59: 51–71.
  93. Fukuhara S., Sako K., Noda K. et al. Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis. Histol. Histopathol. 2010; 25(3): 387–96.
  94. Elice F., Rodeghiero F. Side effects of anti-angiogenic drugs. Thromb. Res. 2012; 129(Suppl. 1): S50–3.
  95. Aichberger K.J., Herndlhofer S., Schernthaner G.H. et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am. J. Hematol. 2011; 86(7): 533–9.
  96. Uniprot for VEGFR1. Available from: http://www.uniprot.org/uniprot/ P17948.
  97. Uniprot for VEGFR2. Available from: http://www.uniprot.org/uniprot/ P35968.
  98. Uniprot for VEGFR3. Available from: http://www.uniprot.org/uniprot/ P35916.
  99. Leppanen V.M., Tvorogov D., Kisko K. et al. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc. Natl. Acad. Sci. U S A 2013; 110(32): 12960–5.
  100. Stuttfeld E., Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life 2009; 61(9): 915–22.
  101. Olsson A.K., Dimberg A., Kreuger J. et al. VEGF receptor signalling — in control of vascular function. Nat. Rev. Mol. Cell Biol. 2006; 7(5): 359–71.
  102. Takahashi H., Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin. Sci. (London) 2005; 109(3): 227–41.
  103. Kamba T., McDonald D.M. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br. J. Cancer 2007; 96(12): 1788–95.
  104. Dy G.K., Adjei A.A. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J. Clin. 2013; 63(4): 249–79.
  105. Baccarani M., Deininger M.W., Rosti G. et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122(6): 872–84.
  106. Soverini S., Colarossi S., Gnani A. et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica 2007; 92(3): 401–4.
  107. Гусарова Г.А., Туркина А.Г., Колошейнова Т.И. и др. Клинические аспекты применения нилотиниба при лечении больных хроническим миелолейкозом в хронической фазе. Гематол. и трансфузиол. 2012; 4: 3–11. [Gusarova G.A., Turkina A.G., Kolosheynova T.I. et al. Clinical aspects of nilotinib administration in management of patients with chronic myeloid leukemia in chronic phase. Gematol. i transfuziol. 2012; 4: 3–11. (In Russ.)].
  108. Лазарева О.В., Костина И.Э., Туркина А.Г. Лекарственно-индуци- рованный пневмонит: редкое осложнение терапии иматиниба мезилатом у больных хроническим миелолейкозом. Клин. онкогематол. 2010; 3(1): 47–52.  [Lazareva O.V., Kostina I.Ye., Turkina A.G. Drug-induced pneumonitis: rare complication of imatinib mesylate therapy in patients with chronic myeloid leukemia. Klin. onkogematol. 2010; 3(1): 47–52. (In Russ.)].
  109. Виноградова О.Ю., Туркина А.Г., Воронцова А.В. и др. Применение дазатиниба у больных в хронической стадии хронического миелолейкоза, резистентных либо не переносящих терапию иматинибом. Тер. арх. 2009; 7: 41–6.  [Vinogradova O.Yu., Turkina A.G., Vorontsova A.V. et al. Dasatinib administration to patients with chronic phase of chronic myeloid leukemia, who are resistant or intolerant to dasatinib. Ter. arkh. 2009; 7: 41–6. (In Russ.)].