Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials

Iwamoto, Naoki; Distler, Jörg H W; Distler, Oliver

doi:10.1007/s11926-010-0142-x

Cited by 40 publications

(20 citation statements)

References 46 publications

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“…The anti-fibrotic effects of TKI are also apparent in humans, prompting their use in clinical trials for systemic sclerosis or idiopathic pulmonary fibrosis [49], [50]. Therefore, we examined the effects of these TKI on the function of MLCs.…”

Section: Discussionmentioning

confidence: 99%

CD90(+) Mesothelial-Like Cells in Peritoneal Fluid Promote Peritoneal Metastasis by Forming a Tumor Permissive Microenvironment

et al. 2014

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The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(−) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, α-smooth muscle actin and fibroblast activated protein-α by the stimulation with TGF-β, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.

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Section: Discussionmentioning

confidence: 99%

CD90(+) Mesothelial-Like Cells in Peritoneal Fluid Promote Peritoneal Metastasis by Forming a Tumor Permissive Microenvironment

et al. 2014

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“…While the effect on PDGF-stimulated fibroblasts seems to be dependent on inhibition of PDGF-R, blockade of TGF- β fibrogenesis is hardly explained by inhibition of TGF- β receptors, which are serine-threonine kinases [150]. Nonetheless c-Abl, the primary target of Imatinib, turned out to be an important noncanonical mediator of TGF- β -induced fibrosis, which otherwise is mediated by the classical Smad pathway [151, 152]. Daniels et al [142] first demonstrated that fibroblasts respond to TGF- β by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGF-R activation.…”

Section: Rational For Using Tki In Cgvhdmentioning

confidence: 99%

Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside

Olivieri

Coluzzi

Attolico

et al. 2011

The Scientific World JOURNAL

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Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβ pathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.

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“…Experience suggests that new antifibrotic treatments can interfere with other disease manifestations, particularly small-vessel vasculopathy associated with Raynaud's phenomenon and digital ulcers. For example, the clinical use of tyrosine kinase inhibitors in SSc seems to be limited by vascular side effects—in particular, massive peripheral oedema, which are far less prominent in the treatment of other diseases such as chronic myeloid leukaemia 22. Thus, optimal antifibrotic treatments for patients with SSc should effectively treat both, fibrosis and vascular disease or, at least, not cause worsening of the patients' vascular manifestations.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis

et al. 2012

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Background Fibrosis and vascular disease are cardinal features of systemic sclerosis (SSc). Stimulators of soluble guanylate cyclase (sGC) are vasoactive drugs that are currently being evaluated in phase III clinical trials for pulmonary arterial hypertension. Objective To study the antifi brotic potency of sGC stimulators. Methods The effect of the sGC stimulator BAY 41-2272 on the release of collagen from dermal fi broblasts was examined. The antifi brotic effects of BAY 41-2272 on prevention and regression of fi brosis in bleomycin-induced dermal fi brosis and in Tsk-1 mice were also studied. Telemetric blood pressure studies in conscious mice were used to study potential hypotensive effects of sGC stimulation. Results sGC stimulation with BAY 41-2272 dosedependently inhibited collagen release in dermal fi broblasts from patients with SSc and healthy individuals. Furthermore, BAY 41-2272 stopped the development of bleomycin-induced dermal fi brosis and skin fi brosis in Tsk-1 mice, preventing dermal and hypodermal thickening, reducing the numbers of myofi broblasts and reducing the hydroxyproline content. In addition, BAY 41-2272 was highly effective in the treatment of established fi brosis in the modifi ed models of bleomycin-induced skin fi brosis and Tsk-1 mice. Treatment with sGC stimulators was well tolerated. Relevant antifi brotic doses of BAY 41-2272 did not affect systemic blood pressure and heart rate in mice.Conclusions These fi ndings demonstrate potent antifi brotic effects and good tolerability of sGC stimulators in various experimental models of SSc. Given their potential vasoactive properties, sGC stimulators may be promising candidates for the dual treatment of fi brosis and vascular disease in SSc.

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Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials

Cited by 40 publications

References 46 publications

CD90(+) Mesothelial-Like Cells in Peritoneal Fluid Promote Peritoneal Metastasis by Forming a Tumor Permissive Microenvironment

CD90(+) Mesothelial-Like Cells in Peritoneal Fluid Promote Peritoneal Metastasis by Forming a Tumor Permissive Microenvironment

Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside

Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis

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