K Fakiha1, J K Coller1, R M Logan2, R J Gibson3, J M Bowen4. 1. Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia. 2. Adelaide Dental School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia. 3. Division of Health Sciences, University of South Australia, Adelaide, SA, 5005, Australia. 4. Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia. joanne.bowen@adelaide.edu.au.
Abstract
PURPOSE: Gastrointestinal mucositis (GIM) is one of the most debilitating side effects of the chemotherapy agent, irinotecan hydrochloride (CPT-11). The toll-like receptor (TLR) pathway is a key mediator implicated in the pathophysiology underlying GIM. The tricyclic antidepressant amitriptyline has been shown to inhibit TLR2 and TLR4 activity in in vitro models. The aim of this study was therefore to investigate the effect of amitriptyline on the development of GIM following CPT-11. METHODS: Male albino Wistar rats were treated with either CPT-11 (125 mg/kg, i.p., n = 18), amitriptyline (20 mg/kg, n = 18), both agents (n = 18), or vehicle control (n = 18) and killed at 6, 48, or 96 h. Differences between groups in measurements of gastrointestinal toxicity (diarrhea and weight loss), mucosal injury (apoptosis and histopathology score), colonic expression of TLRs, and pro-inflammatory cytokines were determined. RESULTS: CPT-11-induced diarrhea and colonic apoptosis were inhibited by amitriptyline at 6 h. However, rats were not protected from weight loss or mucosal injury over the time course of CPT-11-induced GIM. Interleukin-1 beta transcript expression was significantly decreased with amitriptyline treatment at 6 h, although protein expression did not differ between groups. There was no change in TLR4 or TLR2 expression in any group. CONCLUSIONS: Prophylactic amitriptyline was able to inhibit early intestinal damage in this rat model of CPT-11-induced GIM, but exacerbated late-onset injury. These findings do not support use of amitriptyline as an approach for mitigation of GIM in this setting.
PURPOSE:Gastrointestinal mucositis (GIM) is one of the most debilitating side effects of the chemotherapy agent, irinotecan hydrochloride (CPT-11). The toll-like receptor (TLR) pathway is a key mediator implicated in the pathophysiology underlying GIM. The tricyclic antidepressant amitriptyline has been shown to inhibit TLR2 and TLR4 activity in in vitro models. The aim of this study was therefore to investigate the effect of amitriptyline on the development of GIM following CPT-11. METHODS: Male albino Wistar rats were treated with either CPT-11 (125 mg/kg, i.p., n = 18), amitriptyline (20 mg/kg, n = 18), both agents (n = 18), or vehicle control (n = 18) and killed at 6, 48, or 96 h. Differences between groups in measurements of gastrointestinal toxicity (diarrhea and weight loss), mucosal injury (apoptosis and histopathology score), colonic expression of TLRs, and pro-inflammatory cytokines were determined. RESULTS:CPT-11-induced diarrhea and colonic apoptosis were inhibited by amitriptyline at 6 h. However, rats were not protected from weight loss or mucosal injury over the time course of CPT-11-induced GIM. Interleukin-1 beta transcript expression was significantly decreased with amitriptyline treatment at 6 h, although protein expression did not differ between groups. There was no change in TLR4 or TLR2 expression in any group. CONCLUSIONS: Prophylactic amitriptyline was able to inhibit early intestinal damage in this rat model of CPT-11-induced GIM, but exacerbated late-onset injury. These findings do not support use of amitriptyline as an approach for mitigation of GIM in this setting.
Authors: Ewa Obuchowicz; Jan Kowalski; Krzysztof Labuzek; Robert Krysiak; Joanna Pendzich; Zbigniew S Herman Journal: Int J Neuropsychopharmacol Date: 2005-06-20 Impact factor: 5.176
Authors: Philipp Lirk; Ingrid Haller; Barbara Hausott; Shota Ingorokva; Martina Deibl; Peter Gerner; Lars Klimaschewski Journal: Anesth Analg Date: 2006-06 Impact factor: 5.108
Authors: Joanne M Bowen; Rachel J Gibson; Andrea M Stringer; Thong W Chan; Avanita S Prabowo; Adrian G Cummins; Dorothy M K Keefe Journal: Anticancer Drugs Date: 2007-02 Impact factor: 2.248
Authors: Rachel J Gibson; Joanne M Bowen; Mark R B Inglis; Adrian G Cummins; Dorothy M K Keefe Journal: J Gastroenterol Hepatol Date: 2003-09 Impact factor: 4.029
Authors: Maria Luisa P Melo; Gerly A C Brito; Rudy C Soares; Sarah B L M Carvalho; Johan V Silva; Pedro M G Soares; Mariana L Vale; Marcellus H L P Souza; Fernando Q Cunha; Ronaldo A Ribeiro Journal: Cancer Chemother Pharmacol Date: 2007-07-12 Impact factor: 3.333
Authors: Janine S Y Tam; Elise E Crame; Aurelia S Elz; Janet K Coller; Anthony Wignall; Clive A Prestidge; Joanne M Bowen Journal: Cancer Chemother Pharmacol Date: 2022-08-12 Impact factor: 3.288