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Jean-louis Lefaix - One of the best experts on this subject based on the ideXlab platform.
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Current Management for Late Normal Tissue Injury: Radiation-Induced Fibrosis and Necrosis
Seminars in Radiation Oncology, 2007Co-Authors: Sylvie Delanian, Jean-louis LefaixAbstract:Radiation-Induced Fibrosis (RIF) and radionecrosis (RN) are late complications that are usually considered irreversible. Usual management strategy includes eliminating local and general aggravating factors and controlling acute and chronic inflammation with steroids. Thanks to progress in understanding the pathophysiology of these lesions, several lines of treatment have been developed in clinical practice. However, results of clinical studies are difficult to compare because of variations in severity of RIF, method of RIF assessment, availability of efficient therapeutic drugs, treatment duration, and quality of trial design. For moderate established RIF, current management strategy mainly includes (1) anti-inflammatory treatment with corticosteroids or interferon gamma; (2) vascular therapy with pentoxifylline (PTX) or hyperbaric oxygen (HBO); and (3) antioxidant treatment with superoxide dismutase, tocopherol (vitamin E), and, most successfully, with a PTX-vitamin E combination. On the basis of etiology, RN can be managed by (1) anti-inflammatory treatment with corticosteroids and possibly clodronate, (2) vascular therapy with HBO and PTX, (3) antioxidant treatment with a PTX-vitamin E combination, and (4) a PTX–vitamin E–clodronate combination. Controlled randomized trials are now necessary to identify the best treatment at each step of RIF. In the future, these treatments of Fibrosis and necrosis should include targeted drugs (such as growth factors) to take organ specificities into account.
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randomized placebo controlled trial of combined pentoxifylline and tocopherol for regression of superficial Radiation Induced Fibrosis
Journal of Clinical Oncology, 2003Co-Authors: Sylvie Delanian, Raphael Porcher, Saida Ballamekias, Jean-louis LefaixAbstract:Purpose Radiation-Induced Fibrosis (RIF) is a rare morbid complication of radiotherapy, without an established method of management. RIF treatment with a combination of pentoxifylline (PTX) and alpha-tocopherol (vitamin E; Vit E) was recently prompted by the good results of a clinical trial and an animal study. The present double-blind, placebo-controlled, monocentric study was designed to assess the efficacy of this combination in treating RIF sequelae. Patients and methods Twenty-four eligible women with 29 RIF areas involving the skin and underlying tissues were enrolled from December 1998 to April 2000. These patients, previously irradiated for breast cancer, were randomly assigned to four balanced treatment groups: (A) 800 mg/d of PTX and 1,000 U/d of Vit E; (B) PTX plus placebo; (C) placebo plus Vit E; and (D) placebo-placebo. The main end point measure was the relative regression of measurable RIF surface after 6 months of treatment. Assessment was completed by depth (with ultrasonography) and associated symptom measures. Results Twenty-two patients with 27 RIF areas were analyzed at 6 months. Mean RIF surface regression was significant with combined PTX/Vit E versus double placebo (60% +/- 10% v 43% +/- 17%; P =.038). The median slope for the speed of RIF surface area and volume regression was significantly higher for group A than groups B, C, and D. All treatments were well tolerated. Conclusion Six months' treatment of combined PTX/Vit E can significantly reduce superficial RIF. Synergism between PTX and Vit E is likely, as treatment with each drug alone is ineffective, but these results require confirmation in larger series.
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Physiopathology of human superficial Radiation-Induced Fibrosis
Comptes rendus des seances de la Societe de biologie et de ses filiales, 1997Co-Authors: Jean-louis Lefaix, Sylvie Delanian, Bernard DubrayAbstract:La fibrose radio-induite, sequelle tardive des irRadiations therapeutiques ou accidentelles, a ete decrite dans de nombreux tissus et organes comme la peau et les tissus sous-cutanes et le poumon. Basee sur des donnees recentes de radiobiologie cellulaire et moleculaire, cette revue tente de presenter une synthese des differents aspects de la fibrose superficielle humaine: observations cliniques et paracliniques, aspects de radiobiologie clinique, modifications tissulaires, regulations cellulaires et moleculaires, et prise en charge therapeutique. Cependant, les mecanismes conduisant a la fibrose radio-induite superficielle restent a etre elucides.
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Changes of the cutaneous micro-relief in superficial Radiation-Induced Fibrosis: a qualitative study
Bulletin du cancer, 1996Co-Authors: Jean-louis Lefaix, Sylvie Delanian, Bernard Dubray, Giraud P, Berland E, Sahraoui S, Mignot JAbstract:Cutaneous Radiation-Induced Fibrosis (RIF) is characterized by a skin retraction or atrophy, toughness to the palpation and often entails functional limitation. Its clinical evaluation remains poorly quantified. The aim of this study was to propose an analytical method to quantify RIF skin surface with the replica technique. In this preliminary study, we report the qualitative and quantitative evaluation of the cutaneous microrelief in 44 healthy controls and in four patients presenting a superficial RIF, 3 to 20 years after radiotherapy for cancer. The microrelief of these RIF presented an abnormal anisotropy with a parallel reorganization of cutaneous valleys in three cases out of four, suggesting a premature Radiation-Induced ageing of the skin. Each subject being his own control, the relative vertical amplitude of the skin microrelief was +/-15% in control skin. Vertical amplitude was respectively increased by 84% in one inflammatory Fibrosis (3 years after RT), decreased by 18% in one evolutive Fibrosis (6 years after RT), decreased by 26% in one voluminous stabilized Fibrosis (8 years after RT) and decreased by 53% in one atrophic Fibrosis (20 years after RT). The present study suggests that the variations of the microrelief parameters could reflect the RIF evolution. This technique requires a validation in a larger series of patients, including patients with telangiectasia.
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Successful treatment of Radiation-Induced Fibrosis using Cu Zn - SOD and Mn-SOD: An experimental study
International Journal of Radiation Oncology*Biology*Physics, 1996Co-Authors: Jean-louis Lefaix, Sylvie Delanian, François Baillet, Jean-jacques Leplat, Yves Tricaud, Michèle T. Martin, Abraham Nimrod, François DaburonAbstract:Abstract Purpose: To establish how far liposomal copper/zinc superoxide dismutase (Cu/ZnSOD) and manganese superoxide dismutase (MnSOD), respectively, reduce Radiation-Induced Fibrosis (RIF), using a well-characterized pig model of RIF permitting the design of a controlled laboratory experiment. Methods and Materials: In this model of acute localized gamma irRadiation simulating accidental overexposure in humans, three groups of five large white pigs were irradiated using a collimated 192 Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of subcutaneous Fibrosis involving skin and skeletal muscle developed 6 months after irRadiation. One experimental group of five pigs was then injected i.m. with 10 mg/10 kg b.w. of Cu/ZnSOD, twice a week for 3 weeks, and another experimental group of five injected with 10 mg/10 kg b.wt. of MnSOD, three times a week for 3 weeks. Five irradiated control pigs were injected with physiological serum. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Block depth was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 12–14 weeks after completing SOD injections. The density, length, width, and depth of the fibrotic block, and the areas and volume of its projected cutaneous surface were compared before treatment, 1, 3, and 6 weeks thereafter, and at autopsy, 12–14 weeks after treatment ended. Results: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. Whether they were given Cu/Zn- or MnSOD, significant and roughly equivalent softening and shrinking of the fibrotic block were noted in all treated animals between the first week after treatment ended and autopsy, when mean regression was 45% for length and width, 30% for depth, and 70% for are and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar. This replacement of scar tissue by normal tissue in experimental animals and the 50% decrease in the linear dimensions of the scar were comparable to the results obtained in previous clinical studies and highly significant compared to the clinical and autopsy results for the control animals. Conclusions: Our results are striking and comparable to the results obtained in our previous clinical study after liposomal Cu/ZnSOD treatment. To our knowledge, this is the first time that two agents have been shown to reverese the Radiation-Induced fibrotic process in experimental animals and to permit the regeneration of normal tissue in a zone of well-established posirRadiation Fibrosis.
Jean-noël Vallée - One of the best experts on this subject based on the ideXlab platform.
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interactions between tgf β1 canonical wnt β catenin pathway and ppar γ in Radiation Induced Fibrosis
Oncotarget, 2017Co-Authors: Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-noël ValléeAbstract:// Alexandre Vallee 1, 2 , Yves Lecarpentier 3 , Remy Guillevin 4 and Jean-Noel Vallee 2, 5 1 Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France 2 Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France 3 Centre de Recherche Clinique, Grand Hopital de l’Est Francilien (GHEF), Meaux, France 4 DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France 5 CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France Correspondence to: Alexandre Vallee, email: alexandre.g.vallee@gmail.com Keywords: TGF-β, canonical WNT/β-catenin pathway, PPAR γ, Radiation-Induced Fibrosis, myofibroblast Received: June 16, 2017 Accepted: August 17, 2017 Published: September 23, 2017 ABSTRACT Radiation therapy induces DNA damage and inflammation leading to Fibrosis. Fibrosis can occur 4 to 12 months after Radiation therapy. This process worsens with time and years. Radiation-Induced Fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during Fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the Radiation-Induced Fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease Radiation-Induced Fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote Radiation-Induced Fibrosis whereas PPAR γ agonists can prevent Radiation-Induced Fibrosis.
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Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in Radiation-Induced Fibrosis.
Oncotarget, 2017Co-Authors: Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-noël ValléeAbstract:// Alexandre Vallee 1, 2 , Yves Lecarpentier 3 , Remy Guillevin 4 and Jean-Noel Vallee 2, 5 1 Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France 2 Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France 3 Centre de Recherche Clinique, Grand Hopital de l’Est Francilien (GHEF), Meaux, France 4 DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France 5 CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France Correspondence to: Alexandre Vallee, email: alexandre.g.vallee@gmail.com Keywords: TGF-β, canonical WNT/β-catenin pathway, PPAR γ, Radiation-Induced Fibrosis, myofibroblast Received: June 16, 2017 Accepted: August 17, 2017 Published: September 23, 2017 ABSTRACT Radiation therapy induces DNA damage and inflammation leading to Fibrosis. Fibrosis can occur 4 to 12 months after Radiation therapy. This process worsens with time and years. Radiation-Induced Fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during Fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the Radiation-Induced Fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease Radiation-Induced Fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote Radiation-Induced Fibrosis whereas PPAR γ agonists can prevent Radiation-Induced Fibrosis.
Alexandre Vallée - One of the best experts on this subject based on the ideXlab platform.
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interactions between tgf β1 canonical wnt β catenin pathway and ppar γ in Radiation Induced Fibrosis
Oncotarget, 2017Co-Authors: Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-noël ValléeAbstract:// Alexandre Vallee 1, 2 , Yves Lecarpentier 3 , Remy Guillevin 4 and Jean-Noel Vallee 2, 5 1 Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France 2 Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France 3 Centre de Recherche Clinique, Grand Hopital de l’Est Francilien (GHEF), Meaux, France 4 DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France 5 CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France Correspondence to: Alexandre Vallee, email: alexandre.g.vallee@gmail.com Keywords: TGF-β, canonical WNT/β-catenin pathway, PPAR γ, Radiation-Induced Fibrosis, myofibroblast Received: June 16, 2017 Accepted: August 17, 2017 Published: September 23, 2017 ABSTRACT Radiation therapy induces DNA damage and inflammation leading to Fibrosis. Fibrosis can occur 4 to 12 months after Radiation therapy. This process worsens with time and years. Radiation-Induced Fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during Fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the Radiation-Induced Fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease Radiation-Induced Fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote Radiation-Induced Fibrosis whereas PPAR γ agonists can prevent Radiation-Induced Fibrosis.
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Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in Radiation-Induced Fibrosis.
Oncotarget, 2017Co-Authors: Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-noël ValléeAbstract:// Alexandre Vallee 1, 2 , Yves Lecarpentier 3 , Remy Guillevin 4 and Jean-Noel Vallee 2, 5 1 Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France 2 Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France 3 Centre de Recherche Clinique, Grand Hopital de l’Est Francilien (GHEF), Meaux, France 4 DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France 5 CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France Correspondence to: Alexandre Vallee, email: alexandre.g.vallee@gmail.com Keywords: TGF-β, canonical WNT/β-catenin pathway, PPAR γ, Radiation-Induced Fibrosis, myofibroblast Received: June 16, 2017 Accepted: August 17, 2017 Published: September 23, 2017 ABSTRACT Radiation therapy induces DNA damage and inflammation leading to Fibrosis. Fibrosis can occur 4 to 12 months after Radiation therapy. This process worsens with time and years. Radiation-Induced Fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during Fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the Radiation-Induced Fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease Radiation-Induced Fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote Radiation-Induced Fibrosis whereas PPAR γ agonists can prevent Radiation-Induced Fibrosis.
Sang-wook Lee - One of the best experts on this subject based on the ideXlab platform.
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Protective effect of α-lipoic acid against Radiation-Induced Fibrosis in mice.
Oncotarget, 2016Co-Authors: Seung-hee Ryu, Eun-young Park, Sungmin Kwak, Seung-ho Heo, Je-won Ryu, Jin-hong Park, Kyung-chul Choi, Sang-wook LeeAbstract:// Seung-Hee Ryu 1 , Eun-Young Park 1 , Sungmin Kwak 3, 4 , Seung-Ho Heo 2 , Je-Won Ryu 2 , Jin-hong Park 1 , Kyung-Chul Choi 3, 4, * , Sang-wook Lee 1, * 1 Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 2 Institute for Life Sciences, Asan Medical Center, Seoul, Korea 3 Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea 4 Cell Dysfunction Research Center and Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea * These authors contributed equally to this work Correspondence to: Sang-wook Lee, e-mail: lsw@amc.seoul.kr Kyung-Chul Choi, e-mail: choikc75@amc.seoul.kr Keywords: Radiation-Induced Fibrosis, α-lipoic acid, acetylation, NF-κB, PAI-1 Received: July 07, 2015 Accepted: December 05, 2015 Published: January 20, 2016 ABSTRACT Radiation-Induced Fibrosis (RIF) is one of the most common late complications of Radiation therapy. We found that α-lipoic acid (α-LA) effectively prevents RIF. In RIF a mouse model, leg contracture assay was used to test the in vivo efficacy of α-LA. α-LA suppressed the expression of pro-fibrotic genes after irRadiation, both in vivo and in vitro , and inhibited the up-regulation of TGF-β1-mediated p300/CBP activity. Thus, α-LA prevents Radiation-Induced Fibrosis (RIF) by inhibiting the transcriptional activity of NF-κB through inhibition of histone acetyltransferase activity. α-LA is a new therapeutic methods that can be used in the prevention-treatment of RIF.
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SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits Radiation-Induced Fibrosis in mice.
Oncotarget, 2015Co-Authors: Jin-hong Park, Seung-hee Ryu, Kyung-chul Choi, Eun Kyung Choi, Seung Do Ahn, Euisun Park, Sang-wook LeeAbstract:// Jin-hong Park 1 , Seung-Hee Ryu 1 , Eun Kyung Choi 1 , Seung Do Ahn 1 , Euisun Park 3 , Kyung-Chul Choi 2, * , Sang-wook Lee 1, * 1 Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 2 Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Korea 3 Life Science Research Center, SK Chemicals, Seongnam-si, Korea * These authors have contributed equally to this work Correspondence to: Sang-wook Lee, e-mail: lsw@amc.seoul.kr Kyung-Chul Choi, e-mail: choikc75@amc.seoul.kr Keywords: Radiation, Fibrosis, TGF-β1, ALK5, SKI2162 Received: September 17, 2014 Accepted: December 08, 2014 Published: February 17, 2015 ABSTRACT Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented Radiation-Induced Fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro . In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. IrRadiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.
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SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits Radiation-Induced Fibrosis in mice.
Oncotarget, 2015Co-Authors: Jin-hong Park, Seung-hee Ryu, Kyung-chul Choi, Eun Kyung Choi, Seung Do Ahn, Euisun Park, Sang-wook LeeAbstract:Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented Radiation-Induced Fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. IrRadiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.
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Abstract 2494: The protective effect of a novel transforming growth factor-β receptor inhibitor against Radiation-Induced Fibrosis
Tumor Biology, 2011Co-Authors: Jin-hong Park, Seung-hee Ryu, Youn-joo Yang, Sang-wook LeeAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Although Radiation-Induced Fibrosis (RIF) is one of the common sequelae after irRadiation of skin and soft tissue, a protective method was not well investigated. The purpose of present study was to assess the protective effect of a newly developed small molecular inhibitor of transforming growth factor (TGF)-β receptor (ALK5 inhibitor) against RIF in mouse model. BALB/c male mice were irradiated 8 weeks after birth. The left hind limbs of mice received two Radiation doses of 22 Gy, once in a week. Specially designed shielding for the rest of the body was used, and 1-cm thickness bolus was applied over the skin to ensure adequate Radiation dose at the surface of hind leg. After irRadiation, 40 mice were randomly divided into two groups of 20 mice each. Each group was treated with once daily intraperitoneal injections of saline (group 1) or ALK5 inhibitor (group 2, 10 mg/kg/day). RIF was assessed by leg contraction test using specially designed Lucite jig under anesthesia every 2 weeks for 6-16 weeks after irRadiation. The length of the extended irradiated leg was compared with the contralateral unirradiated leg. Early and late skin reactions were scored by grading system. Early skin reaction was measured every week for first 4 weeks, and late skin reaction was evaluated at 16 weeks after irRadiation. The ALK5 inhibitor was well tolerated, and no toxic effects related to the drug were observed. There were no significant differences in the average of body weight (g) between the two groups during treatment; 22.76 vs. 23.34 in 6-week (p=0.09), 25.73 vs. 26.05 in 10-week (p=0.466), and 28.54 vs. 28.41 in 13-week (p=0.868). The acute skin reaction was almost identical between the two groups. All mice showed moist desquamation for most of hind limb in 4 weeks after irRadiation, and no significant skin necrosis was observed in both two groups during acute phase. The leg contraction test showed significant protective effect in group 2. The average length of the irradiated leg (percent of the contralateral leg) was significantly lower in group 1 from 6-16 weeks, and the differences of the contracture between the two groups tended to increase with time; 92.46% vs. 96.07% in 6-week (p
Shai Yarkoni - One of the best experts on this subject based on the ideXlab platform.
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amelioration of Radiation Induced Fibrosis inhibition of transforming growth factor β signaling by halofuginone
Journal of Biological Chemistry, 2004Co-Authors: Sandhya Xavier, Ester Piek, Ayelet M Samuni, Angelina Felici, Makiko Fujii, Kathleen C Flanders, Delphine Javelaud, Alain Mauviel, Michael Reiss, Shai YarkoniAbstract:Abstract Radiation-Induced Fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing Radiation. Transforming growth factor-β (TGF-β) has been proposed to be critical in tissue repair mechanisms resulting from Radiation injury. Previously, we showed that interruption of TGF-β signaling by deletion of Smad3 results in resistance to Radiation-Induced injury. In the current study, a small molecular weight molecule, halofuginone (100 nm), is demonstrated by reporter assays to inhibit the TGF-β signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-β type II receptor (TβRII). Attenuation of TβRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-β-Induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 μg/mouse/day) efficacy was assessed using ionizing Radiation-Induced (single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened Radiation-Induced Fibrosis. The effectiveness of Radiation treatment (2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-β signal pathway and show that halofuginone may lessen Radiation-Induced Fibrosis in humans.
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Amelioration of Radiation-Induced Fibrosis INHIBITION OF TRANSFORMING GROWTH FACTOR-β SIGNALING BY HALOFUGINONE
The Journal of biological chemistry, 2004Co-Authors: Sandhya Xavier, Ester Piek, Ayelet M Samuni, Angelina Felici, Makiko Fujii, Kathleen C Flanders, Delphine Javelaud, Alain Mauviel, Michael Reiss, Shai YarkoniAbstract:Radiation-Induced Fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing Radiation. Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from Radiation injury. Previously, we showed that interruption of TGF-beta signaling by deletion of Smad3 results in resistance to Radiation-Induced injury. In the current study, a small molecular weight molecule, halofuginone (100 nm), is demonstrated by reporter assays to inhibit the TGF-beta signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-beta type II receptor (TbetaRII). Attenuation of TbetaRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-beta-Induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 microg/mouse/day) efficacy was assessed using ionizing Radiation-Induced (single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened Radiation-Induced Fibrosis. The effectiveness of Radiation treatment (2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen Radiation-Induced Fibrosis in humans.
