Effects of 5-fluorouracil on oral barrier functions

Sammanfattning: Many anticancer drugs, e.g. 5-fluorouracil (5-FU), may cause oral mucositis and ulcerations. These adverse reactions can be severe and debilitating to the patient, and adjustment of the cancer treatment may be necessary. Efforts to develop reliable clinical protocols to relieve the oral side effects have so far been disappointing. Thus, further knowledge regarding the pathophysiology behind these lesions is warranted. This thesis focused on some influences of 5-FU on major oral barrier functions, the oral epithelium, the local immune defence and the microflora. Rats were treated with 5-FU (30 mg/kg; 50 mg/kg) i.v. In one experiment, the probiotic bacteria Lactobacillus plantarum 299v, was delivered in the drinking water during 5-FU treatment, to modify bacterial overgrowth. After the animals were sacrificed, biopsies were taken. Oral keratinocytes were investigated for 5-FU induced mode of cell death. Analysis was performed by flow cytometry, vital dye exclusion test, the TUNEL method and ultrastructural analysis. The number of local immunocompetent cells of the oral mucosa was compared with the number of similar cell populations of the dental pulp. MHC class II molecule expressing cells of the buccal epithelium and dental pulp were assessed for the capacity to induce a ConA stimulated T cell proliferation. Changes in bacterial homeostasis of the oral cavity and intestine were evaluated and predominating groups of facultative anaerobes were identified by colony morphology and gram staining appearance. The cervical and mesenteric lymph nodes were analysed for any numbers of viable bacteria. 5-FU treatment caused alterations in the keratinocytes consistent with autophagic degeneration. The local cellular immune defence of the oral mucosa and dental pulp was affected. 5-FU caused an increase in the total number of bacteria and the number of facultative anaerobes in the oral cavity and in the number of facultative anaerobes in the intestine. The proportions of facultative gram-negative rods increased. Bacteria increased in numbers in both the cervical and mesenteric lymph nodes. These findings reinforce the oral cavity, along with the gastrointestinal tract, as an important source for bacterial dissemination. L. plantarum 299v did to some extent normalise 5-FU induced disturbances in the oral and intestinal microbiota and improve the well-being of the animals. Conclusions: Influences of 5-FU on oral barrier functions were demonstrated. 5-FU may disrupt the oral epithelium, decrease the immune response and disturb the microflora. The findings indicate that the cervical lymph nodes may be an important route for bacterial dissemination from the oral cavity. Probiotic bacteria may have a positive effect on some of these functions.

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