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ORIGINAL RESEARCH ARTICLE

Chemotherapy-Induced Mucositis Is Associated with Changes in Proteolytic Pathways

Jonathan Leblond^*, Florence Le Pessot, Aurélie Hubert-Buron^*, Célia Duclos, Jacques Vuichoud, Magali Faure, Denis Breuillé, Pierre Déchelotte^* and Moïse Coëffier^*,1

^* Appareil Digestif Environnement Nutrition (EA3234), Institut Hospitalo-Universitaire de Recherche Biomédicale and Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP23), University of Rouen and Rouen University Hospital, France; Service d’anatomie pathologique, Rouen University Hospital, France; and the Nestlé Research Center, Nutrition and Health Department, Lausanne, Switzerland

To whom requests for reprints should be addressed at ¹ ADEN (EA3234, IFRMP23), 22 boulevard Gambetta, 76183 Rouen cedex 1, France. E-mail: moise.coeffier{at}univ-rouen.fr or moise.coeffier{at}chu-rouen.fr

Mucositis, a common toxic side effect of chemotherapy, is characterized by an arrest of cell proliferation and a loss of gut barrier function, which may cause treatment reduction or withdrawal. Gut integrity depends on nutritional and metabolic factors, including the balance between protein synthesis and proteolysis. The effects of methotrexate (MTX; a frequently used chemotherapeutic agent) on intestinal proteolysis and gut barrier function were investigated in rats. Male Sprague-Dawley rats received 2.5 mg/kg of MTX subcutaneously during 3 days and were euthanized at Day 4 (D4) or Day 7 (D7). We observed at D4 that MTX induced mucosal damage and increased intestinal permeability (7-fold) and the mucosal concentration of interleukin (IL)-1β and IL-6 (4- to 6-fold). In addition, villus height and glutathione content significantly decreased. Intestinal proteolysis was also affected by MTX as cathepsin D activity increased at D4, whereas chymotrypsin-like proteasome activity decreased and calpain activities remained unaffected. At D7, cathepsin D activity was restored to control levels, but proteasome activity remained reduced. This disruption of proteolysis pathways strongly contributed to mucositis and requires further study. Lysosomal proteolytic activity may be considered the main proteolytic pathway responsible for alteration of mucosal integrity and intestinal permeability during mucositis, as cathespin D activity was found to be correlated with mucosal atrophy and intestinal permeability. Proteasome regulation could possibly be an adaptive process for survival. Future investigation is warranted to target proteolytic pathways with protective nutritional or pharmacological therapies during mucositis.

Key Words: chemotherapy • mucositis • gut barrier • proteolysis • methotrexate