Chemotherapy-induced mucositis development in a murine model of colitis-associated colorectal cancer

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.

Keywords:

• 5-FU
• chemotherapy
• colitis-associated colorectal cancer
• cancer
• IBD
• mucositis
• mouse model

Disclosure statement

The authors report no conflict of interest.

Data availability

The data that support the findings of this study are available from the corresponding author, (SM), upon reasonable request.