BACKGROUND: KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator-related symptoms. METHODS: We examined the effects of three KIT TKI, imatinib, nilotinib, and midostaurin, on IgE-dependent mediator release in normal human blood basophils and cultured cord blood cell-derived MC, and on spontaneous histamine secretion in the MC leukaemia cell line HMC-1 and the basophil cell line KU812. RESULTS: The multi-kinase inhibitor midostaurin that interacts with KIT and protein kinase C was found to counteract anti-IgE-induced mediator release in blood basophils and cultured cord blood cell-derived MC in all samples examined. By contrast, no effects of imatinib or nilotinib on histamine secretion in basophils or MC were found. The effects of midostaurin on histamine release were dose-dependent and occurred at pharmacologic concentrations (IC(50) 10-100 nm). Midostaurin was also found to inhibit the IgE-dependent up-regulation of CD63 on cultured cord blood cell-derived human MC, but did not inhibit IgE-dependent up-regulation of CD63 or CD203c in human blood basophils. CONCLUSION: Midostaurin may be a beneficial drug in aggressive systemic mastocytosis not only because of its growth-inhibitory effects but also because of its additional effects on activation and mediator release in MC and basophils.
BACKGROUND:KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator-related symptoms. METHODS: We examined the effects of three KIT TKI, imatinib, nilotinib, and midostaurin, on IgE-dependent mediator release in normal human blood basophils and cultured cord blood cell-derived MC, and on spontaneous histamine secretion in the MC leukaemia cell line HMC-1 and the basophil cell line KU812. RESULTS: The multi-kinase inhibitor midostaurin that interacts with KIT and protein kinase C was found to counteract anti-IgE-induced mediator release in blood basophils and cultured cord blood cell-derived MC in all samples examined. By contrast, no effects of imatinib or nilotinib on histamine secretion in basophils or MC were found. The effects of midostaurin on histamine release were dose-dependent and occurred at pharmacologic concentrations (IC(50) 10-100 nm). Midostaurin was also found to inhibit the IgE-dependent up-regulation of CD63 on cultured cord blood cell-derived human MC, but did not inhibit IgE-dependent up-regulation of CD63 or CD203c in human blood basophils. CONCLUSION:Midostaurin may be a beneficial drug in aggressive systemic mastocytosis not only because of its growth-inhibitory effects but also because of its additional effects on activation and mediator release in MC and basophils.
Authors: P Valent; C Akin; K Hartmann; T I George; K Sotlar; B Peter; K V Gleixner; K Blatt; W R Sperr; P W Manley; O Hermine; H C Kluin-Nelemans; M Arock; H-P Horny; A Reiter; J Gotlib Journal: Ann Oncol Date: 2017-10-01 Impact factor: 32.976
Authors: Tariq I Mughal; Jason Gotlib; Ruben Mesa; Steffen Koschmieder; H Jean Khoury; Jorge E Cortes; Tiziano Barbui; Rüdiger Hehlmann; Michael Mauro; Susanne Saussele; Jerald P Radich; Richard A Van Etten; Giuseppe Saglio; Srdnan Verstovek; Robert Peter Gale; Omar Abdel-Wahab Journal: Leuk Res Date: 2018-02-14 Impact factor: 3.156
Authors: D J DeAngelo; T I George; A Linder; C Langford; C Perkins; J Ma; P Westervelt; J D Merker; C Berube; S Coutre; M Liedtke; B Medeiros; D Sternberg; C Dutreix; P-A Ruffie; C Corless; T J Graubert; J Gotlib Journal: Leukemia Date: 2017-07-24 Impact factor: 11.528
Authors: Peter Valent; Cem Akin; Karin Hartmann; Gunnar Nilsson; Andreas Reiter; Olivier Hermine; Karl Sotlar; Wolfgang R Sperr; Luis Escribano; Tracy I George; Hanneke C Kluin-Nelemans; Celalettin Ustun; Massimo Triggiani; Knut Brockow; Jason Gotlib; Alberto Orfao; Lawrence B Schwartz; Sigurd Broesby-Olsen; Carsten Bindslev-Jensen; Petri T Kovanen; Stephen J Galli; K Frank Austen; Daniel A Arber; Hans-Peter Horny; Michel Arock; Dean D Metcalfe Journal: Cancer Res Date: 2017-03-02 Impact factor: 12.701