Effects of 5-fluorouracil on oral barrier functions

Abstract

Many anticancer drugs, e.g. 5-fluorouracil (5-FU), may cause oral mucositis andulcerations. These adverse reactions can be severe and debilitating to the patient, andadjustment of the cancer treatment may be necessary. Efforts to develop reliable clinicalprotocols to relieve the oral side effects have so far been disappointing. Thus, furtherknowledge regarding the pathophysiology behind these lesions is warranted.This thesis focused on some influences of 5-FU on major oral barrier functions, the oralepithelium, 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 probioticbacteria Lactobacillus plantarum 299v, was delivered in the drinking water during 5-FUtreatment, to modify bacterial overgrowth.After the animals were sacrificed, biopsies were taken. Oral keratinocytes wereinvestigated for 5-FU induced mode of cell death. Analysis was performed by flowcytometry, vital dye exclusion test, the TUNEL method and ultrastructural analysis. Thenumber of local immunocompetent cells of the oral mucosa was compared with the numberof similar cell populations of the dental pulp. MHC class II molecule expressing cells of thebuccal epithelium and dental pulp were assessed for the capacity to induce a ConA stimulatedT cell proliferation. Changes in bacterial homeostasis of the oral cavity and intestine wereevaluated and predominating groups of facultative anaerobes were identified by colonymorphology and gram staining appearance. The cervical and mesenteric lymph nodes wereanalysed 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 facultativeanaerobes in the oral cavity and in the number of facultative anaerobes in the intestine. Theproportions of facultative gram-negative rods increased. Bacteria increased in numbers inboth 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 andintestinal microbiota and improve the well-being of the animals.Conclusions: Influences of 5-FU on oral barrier functions were demonstrated. 5-FU maydisrupt the oral epithelium, decrease the immune response and disturb the microflora. Thefindings indicate that the cervical lymph nodes may be an important route for bacterial disseminationfrom the oral cavity. Probiotic bacteria may have a positive effect on some ofthese functions.