Modulation of radiation-induced oral mucositis by thalidomide

Oral mucositis is a common, dose-limiting early side effect of radio(chemo)therapy for head-and-neck tumors. The epithelial radiation response is accompanied by changes in the inflammatory signaling cascades mediated by the transcription factor nuclear factor-kappa B (NF-kappa B). The present study was initiated to determine the effect of the NF-kappa B inhibitor thalidomide on the clinical manifestation of oral mucositis in the established mouse tongue model. Treatment protocols comprised single dose irradiation and daily fractionated irradiation (5 fractions of 3 Gy/week) over 1 (days 0-4) or 2 weeks (days 0-4, 7-11), alone or in combination with daily thalidomide application (100 mg/kg intraperitoneally) over varying time intervals. Fractionation protocols were terminated by graded local radiation doses (day 7/14) to generate full dose-effect curves. Tongue epithelial ulcerations, corresponding to confluent mucositis, served as the clinically relevant endpoint. Thalidomide application did not show a significant radioprotective potential when administered in combination with single dose irradiation. Thalidomide in combination with one week of fractionated irradiation significantly increased the isoeffective top-up doses. Similar results were observed during two weeks of fractionated irradiation in all but one experiment. Thalidomide treatment demonstrated a significant mucositis-ameliorating effect during fractionated irradiation, which is likely to result from NF-kappa B inhibition. However, further mechanistic studies are required to define the underlying mechanisms of the observed mucoprotective effect.