Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Cerny-Reiterer, S; Rabenhorst, A; Stefanzl, G; Herndlhofer, S; Hoermann, G; Müllauer, L; Baumgartner, S; Beham-Schmid, C; Sperr, WR; Mannhalter, C; Sill, H; Linkesch, W; Arock, M; Hartmann, K; Valent, P.
Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia.
Oncotarget. 2015; 6(5):3071-3084
Doi: 10.18632/oncotarget.3074
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- Co-Autor*innen der Med Uni Graz
- Beham-Schmid Christine
- Linkesch Werner
- Sill Heinz
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- Abstract:
- Although mast cells (MC) play an important role in allergic reactions, their physiologic role remains unknown. In mice, several models of MC-deficiency have been developed. However, no comparable human model is available. We examined the in vitro- and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC50: 0.01 µM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0 ± 11.1 ng/ml; post-therapy: 3.4 ± 1.8, p<0.01). Other myeloid lineages, known to develop independently of KIT, were not affected by imatinib-therapy. Imatinib also produced a substantial decrease in MC-development in mice. However, no clinical syndrome attributable to drug-induced MC-deficiency was recorded in our CML patients. Together, imatinib suppresses MC production in vitro and in vivo. However, drug-induced MC depletion is not accompanied by adverse clinical events, suggesting that MC are less relevant to homeostasis in healthy tissues than we assumed so far.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Aged -
- Animals -
- Antineoplastic Agents - adverse effects
- Cell Line, Tumor -
- Dose-Response Relationship, Drug -
- Female -
- Gene Expression Regulation, Enzymologic -
- Gene Expression Regulation, Neoplastic -
- Humans -
- Imatinib Mesylate - adverse effects
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive - immunology
- Male -
- Mast Cells - drug effects
- Mast Cells - enzymology
- Mast Cells - immunology
- Mice, Inbred BALB C -
- Mice, Inbred C57BL -
- Middle Aged -
- Protein Kinase Inhibitors - adverse effects
- Proto-Oncogene Proteins c-kit - antagonists & inhibitors
- Proto-Oncogene Proteins c-kit - genetics
- Proto-Oncogene Proteins c-kit - metabolism
- Time Factors -
- Treatment Outcome -
- Tryptases - genetics
- Tryptases - metabolism
- Xenograft Model Antitumor Assays -
- Find related publications in this database (Keywords)
- Mast Cells
- KIT
- Imatinib
- Mast Cell Deficiency