Lauren C Chartier1,2, Gordon S Howarth1,2,3, Suzanne Mashtoub1,2,4. 1. Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, Australia. 2. Gastroenterology Department, Women's and Children's Hospital, North Adelaide, Australia. 3. School of Animal & Veterinary Sciences, The University of Adelaide, Roseworthy, Australia. 4. School of Medicine, The University of Western Australia, Murdoch, Australia.
Abstract
Objectives: Ulcerative colitis is an incurable inflammatory bowel disease that increases the risk of colorectal cancer (CRC). 5-Fluorouracil (5-FU) is the predominant chemotherapy for CRC patients; however, undesirable side-effects, including mucositis, are common. This study utilised 5-FU-treatment in a model of colitis-associated CRC to develop a pre-clinical setting of intestinal mucositis coincident with manifestation of CRC.Materials/methods: On day 0, female C57BL/6 mice (n = 10/group); (1) saline control, (2) AOM/DSS control, or (3) AOM/DSS + 5-FU were injected with saline or AOM (i.p; 7.4 mg/kg). Groups 2 and 3 underwent cycles of seven days 2%w/v DSS followed by 14 days plain water. After three cycles, 5-FU was administered weekly (i.p; 75 mg/kg) to group 3 for five weeks. Clinical indicators were measured daily and colonoscopy performed at four time-points. Mice were euthanized at 13 weeks (day 91). Intestinal sections were collected for histological and biochemical analyses. p < .05 was considered significant. Results: AOM/DSS resulted in bodyweight loss, increased disease activity index, colitis-severity and tumour number compared to saline controls (p < .05). 5-FU-treatment in AOM/DSS mice decreased bodyweight and disease activity index at selected time-points compared to AOM/DSS controls (p < .05). 5-FU did not impact colitis-severity or overall tumour burden; although, resulted in fewer small tumours compared to AOM/DSS controls (<2mm; p < .05). AOM/DSS increased histological severity scores in intestinal sections (p < .05), however, 5-FU-treatment did not further increase histologically-assessed disease severity (p > .05). Conclusion: Weekly 5-FU administration at a dose of 75 mg/kg was insufficient to reduce overall tumour burden or induce intestinal mucositis in the AOM/DSS mouse model.
Objectives:Ulcerative colitis is an incurable inflammatory bowel disease that increases the risk of colorectal cancer (CRC). 5-Fluorouracil (5-FU) is the predominant chemotherapy for CRCpatients; however, undesirable side-effects, including mucositis, are common. This study utilised 5-FU-treatment in a model of colitis-associated CRC to develop a pre-clinical setting of intestinal mucositis coincident with manifestation of CRC.Materials/methods: On day 0, female C57BL/6 mice (n = 10/group); (1) saline control, (2) AOM/DSS control, or (3) AOM/DSS + 5-FU were injected with saline or AOM (i.p; 7.4 mg/kg). Groups 2 and 3 underwent cycles of seven days 2%w/v DSS followed by 14 days plain water. After three cycles, 5-FU was administered weekly (i.p; 75 mg/kg) to group 3 for five weeks. Clinical indicators were measured daily and colonoscopy performed at four time-points. Mice were euthanized at 13 weeks (day 91). Intestinal sections were collected for histological and biochemical analyses. p < .05 was considered significant. Results: AOM/DSS resulted in bodyweight loss, increased disease activity index, colitis-severity and tumour number compared to saline controls (p < .05). 5-FU-treatment in AOM/DSS micedecreased bodyweight and disease activity index at selected time-points compared to AOM/DSS controls (p < .05). 5-FU did not impact colitis-severity or overall tumour burden; although, resulted in fewer small tumours compared to AOM/DSS controls (<2mm; p < .05). AOM/DSS increased histological severity scores in intestinal sections (p < .05), however, 5-FU-treatment did not further increase histologically-assessed disease severity (p > .05). Conclusion: Weekly 5-FU administration at a dose of 75 mg/kg was insufficient to reduce overall tumour burden or induce intestinal mucositis in the AOM/DSS mouse model.
Authors: Alexander T Sougiannis; Brandon N VanderVeen; J Mark Davis; Daping Fan; E Angela Murphy Journal: Am J Physiol Gastrointest Liver Physiol Date: 2021-01-20 Impact factor: 4.052