RESUMO
Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-ß (TGF-ß). Western blotting of proteins involved in fibroblast contractility and TGF-ß signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-ß in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-ß, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis.
Assuntos
Antioxidantes/uso terapêutico , Fitoterapia , Quercetina/uso terapêutico , Protetores contra Radiação/uso terapêutico , Radiodermite/prevenção & controle , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Biotransformação , Carcinoma de Células Escamosas/radioterapia , Forma Celular , Colágeno/biossíntese , Colágeno/genética , Ensaio de Unidades Formadoras de Colônias , Avaliação Pré-Clínica de Medicamentos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Fibroblastos/efeitos da radiação , Fibrose , Genes Reporter , Membro Posterior/efeitos da radiação , Humanos , Camundongos , Camundongos Endogâmicos C3H , Células NIH 3T3/efeitos dos fármacos , Células NIH 3T3/fisiologia , Células NIH 3T3/efeitos da radiação , Quercetina/administração & dosagem , Quercetina/farmacocinética , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/farmacocinética , Radiodermite/etiologia , Radioterapia/efeitos adversos , Distribuição Aleatória , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Neoplasias Cutâneas/radioterapia , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/efeitos da radiação , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genéticaRESUMO
Radiotherapy used in the treatment of bone and soft tissue sarcomas in pediatric patients often results in undesirable growth plate damage. Radioprotectants may hold promise in the selective protection of growth plate tissue in this setting. In an animal model, the hypothesis tested was that pentoxifylline, selenium, or misoprostol, used in combination with amifostine, would significantly reduce longitudinal growth loss during one radiation dose exposure to a greater extent than the protection provided by only amifostine without increased morbidity or mortality or adverse effects on bone mineral density. Amifostine alone and in combination with each of the other radioprotectants resulted in limb discrepancy reduction to levels significantly less than radiated controls. The tibial length discrepancy in the selenium and amifostine group was 12.1 +/- 0.8%, less than the 15.5 +/- 2.6% tibial length discrepancy in the animals treated with amifostine alone, and less than the mean 18.8% tibial length discrepancy in the radiated limbs without radioprotection. There were no adverse effects on bone density in any group, but the selenium and amifostine group showed some increased mortality. Combinations of amifostine with these radioprotectants show efficacy in growth plate radioprotection and therefore warrant additional study in a clinically relevant fractionated model.