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These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated <jats:italic>in vitro<\/jats:italic> on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> experiments provided promising insights that melatonin may be used as a preventive and\/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.<\/jats:p>","DOI":"10.1371\/journal.pone.0307414","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T17:31:26Z","timestamp":1725384686000},"page":"e0307414","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids"],"prefix":"10.1371","volume":"19","author":[{"given":"Karsten","family":"Peters","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"Lerma 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