This article appears in the following Rheumatology issue: Update in systemic sclerosis [View the issue table of contents]
Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis
1Department for Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany and 2Department of Rheumatology, Center of Experimental Rheumatology and Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
Correspondence to: J. H. W. Distler, Department of Internal Medicine 3, University of Erlangen-Nuremberg, Germany. E-mail: joerg.distler{at}uk-erlangen.de
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Abstract |
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Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparation.
KEY WORDS: Imatinib, Dasatinib, Nilotinib, c-Abl, Src, Plate-derived growth factor, Transforming growth factor-β, Scleroderma, Fibrosis, Bleomycin
Submitted 30 April 2008; Accepted 19 June 2008