Modulation of radiation-induced Oral mucositis (mouse) by dermatan sulfate: Effects on differentiation processes

Purpose: During head-and-neck cancer (HNC) radio-chemotherapy (RChT) oral mucositis (OM) is the most frequently dose-limiting early side effect. Changes in the differentiation processes of epithelial cells are thought to be effective in the molecular pathogenesis of this ulcerative epithelial formation. Application of Dermatan Sulphate (DS) during fractionated irradiation (IR) has been shown to significantly increase the radiation tolerance of the oral mucosa. In the designed animal model, it was aimed to investigate the mechanism of oral epithelial differentiation by IR alone or in combination with DS treatment. Materials and Methods: Both male/female 140 mice from the C3H/Neu strain with the normal immune system were irradiated over two weeks with daily fractionated 3 Gray (Gy) with total dose 30Gy/10fraction, IR alone and additional DS treatment (IR+DS). The mouse group (n = 3) was sacrificed every two days for 14 days in both experimental arms. Samples were stained with cell proliferation marker p16, differentiation marker p21 and cytokeratin (SK) antibody indicating cellular skeletal integrity according to tissue-specific protocols. Statistical analysis was performed with SPSS 17 by one-way ANOVA test. Results: In p16 analysis, no significant difference was found between IR alone and IR+DS arms in the germinal (proliferation) layer. In p21 analysis, the difference between IR alone and IR+DS was significant (p <0.05) for the functional (differentiation) layer, and the number of p21 positive cells decreased in the DS-treated arm. In cytokeratin antibody analysis, CK positive cells were not below the normal level for germinal and functional layer and in both experimental arms and superiority was found in DS arm (p <0.05). When the epithelial thicknesses were examined, it was found that the mean epithelial thickness was higher in the IR+DS arm than the IR alone arm, but no significant difference was observed for the average cell numbers. Conclusion: The oral mucosal protective property of Dermatan Sulphate prevents quality cell loss and provides mechanical integrity by combining effects that lead to inhibition of cellular differentiation and increased intracellular bonds, rather than stimulating proliferation. Keywords: oral mucositis; mouse model; dermatan sulfate; fractionation; proliferation, differantiaiton; cellular junctions