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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Thalidomide treatment demonstrated a significant 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.
Platform Radiooncology and Nuclear Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine of Vienna, Vienna, Austria.|Department of Radiotherapy, ATRAB - Applied and Translational Radiotherapy, Medical University of Vienna/General Hospital of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Katharina
K
Frings
Department of Radiotherapy, ATRAB - Applied and Translational Radiotherapy, Medical University of Vienna/General Hospital of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.|Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna, Austria.
Sylvia
S
Gruber
Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna, Austria.
Peter
P
Kuess
Platform Radiooncology and Nuclear Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine of Vienna, Vienna, Austria.
Miriam
M
Kleiter
Department of Radiotherapy, ATRAB - Applied and Translational Radiotherapy, Medical University of Vienna/General Hospital of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. Wolfgang.Doerr@meduniwien.ac.at.|Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna, Austria. Wolfgang.Doerr@meduniwien.ac.at.
Wolfgang
W
Dörr
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D008809:Mice, Inbred C3H; D009061:Mouth Mucosa / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011832:Radiation Injuries / Q000188:drug therapy* / Q000473:pathology*; D013280:Stomatitis / Q000188:drug therapy* / Q000473:pathology*; D013792:Thalidomide / Q000008:administration & dosage*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D013792:Thalidomide
Mouse model; NF-κB; Oral mucositis; Radiotherapy; Thalidomide