Modulation of radiation-induced oral mucositis by thalidomide : Preclinical studies.

Abstract

Oral mucositis is acommon, 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-kappaB (NF-κB). The present study was initiated to determine the effect of the NF-κB 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 3Gy/week) over 1 (days 0-4) or 2weeks (days 0-4, 7-11), alone or in combination with daily thalidomide application (100mg/kg intraperitoneally) over varying time intervals. Fractionation protocols were terminated by graded local radiation doses (day7/14) to generate full dose-effect curves. Tongue epithelial ulcerations, corresponding to confluent mucositis, served as the clinically relevant endpoint. Thalidomide application did not show asignificant 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 asignificant mucositis-ameliorating effect during fractionated irradiation, which is likely to result from NF-κB inhibition. However, further mechanistic studies are required to define the underlying mechanisms of the observed mucoprotective effect.