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- Peters, Karsten
(författare)
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Experimental Disruption of Intestinal Mucosal Homeostasis : Exploring the Protective Potential of Melatonin and Misoprostol
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The intestinal mucosa serves as a protective layer that separates the intestinal contents from the underlying tissues. It restricts harmful substances, pathogens, and undigested particles from entering the bloodstream. This mucosa also facilitates selective absorption of nutrients, electrolytes, and fluids, allowing essential substances to pass while maintaining a defense against potential threats. The integrity of the mucosa can be disrupted, such as in diseases or by off-target toxicities of chemotherapeutic drugs. A dysfunctional intestinal mucosa can result in inflammation, altered epithelial secretory and absorptive functions, as well as an increased mucosal permeability that may enable bacterial translocation. Chemotherapy-induced intestinal side effects may lead to dose reduction or even discontinuation of the treatment, but also decreasing the patient’s quality of life. The aim of this thesis was to explore the protective potential of melatonin and misoprostol on experimental disruption of small intestinal mucosal permeability and chemotherapy-induced mucositis. In Papers I and II an increase in intestinal mucosal permeability was induced by perfusing the jejunal segment with the surfactant sodium dodecyl sulfate (SDS) in rats. Melatonin and misoprostol were found to mitigate the induced increase in permeability. In Paper II it was shown that the melatonin receptor antagonist luzindole completely abolished the protective effect of melatonin on SDS-induced increase in mucosal permeability, showing that the effect of melatonin is receptor-mediated. In Papers III and IV off-target intestinal toxicity of the chemotherapeutic agents doxorubicin (DOX) and 5-fluorouracil (5-FU) were evaluated. In Paper III the progression of intestinal mucositis during seven consecutive days after a single injection of DOX was monitored. It was found that villus atrophy was most distinct after three days. In addition, within the first 24 hours after administration of DOX the most pronounced effect on a decrease in cell proliferation and an increase in crypt cell apoptosis was observed. In Paper IV it was found that daily administration of melatonin fully prevented villus atrophy and reduced the number of apoptotic crypts cells induced by a single injection of 5-FU. Administration of misoprostol increased colonic water contents but had no effect on 5-FU-induced villus atrophy or apoptosis. Furthermore, melatonin reduced 5-FU-induced cytotoxicity in murine intestinal organoids.In conclusion, the results suggest that melatonin might be a potential candidate for supportive therapy in diseases affecting the small intestinal mucosal barrier and in chemotherapy-induced mucositis.
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| 2. |
- Kullenberg, Fredrik
(författare)
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Anthracyclines : Toxicity and chemotherapy-induced mucositis
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Anthracyclines belong to a class of cytostatic compounds that are commonly used to treat various types of cancers, including lymphoma, breast cancer and primary liver cancer. The aim of this thesis was to study how two anthracyclines, doxorubicin and idarubicin, induced cytotoxicity in tumor cells, as well as their off-target effect on the gastrointestinal system. In Paper I, we exposed four different cancer cell lines to various concentrations of doxorubicin in two different formulations, and measured the cell viability and how much doxorubicin was taken up by the cells. We found that the cell lines differed in their uptake and sensitivity, and that the most resistant cell line had an intracellular exposure of doxorubicin that was about 100 times lower when compared to the more sensitive cell lines. To study the off-target gastrointestinal toxicity, we dosed rats with doxorubicin and studied how chemotherapy-induced mucositis developed during seven days in Paper II. The main effect parameter was intestinal villus atrophy, which was most severe after three days. This was preceded by an increased cell death and decreased proliferation in the crypts, which occurred within the first day after doxorubicin exposure. To study how different cytostatic drugs affected chemotherapy-induced mucositis, and to what extent they caused diarrhea, rats were dosed with one of six different chemotherapies, including doxorubicin and idarubicin, in Paper III. All selected chemotherapies caused similar villus atrophy three days after dosing, but only a third, including idarubicin, caused clear diarrhea. In paper IV the objective was to treat or prevent idarubicin-induced mucositis and diarrhea, by using the anti-inflammatory drugs anakinra and/or dexamethasone. Anakinra alone stopped the diarrhea, while the combination of anakinra and dexamethasone prevented villus atrophy. These positive effects encourage further investigations into the use of anakinra and dexamethasone as supportive therapies for chemotherapy-induced mucositis and diarrhea.The overall long-term impact of the different studies in this thesis is to increase the specific anti-tumoral effect of chemotherapies, while also alleviating the adverse effects. This would improve quality-of-life and treatment outcomes of cancer patients.
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