EUROPEAN RADIATION RESEARCH 2012

The role of apoptosis in the oral mucositis – experimental studies

17 Oct 2012, 16:37

1m

Poster Hall (Vietri sul Mare)

poster preferred Normal Tissue Damage Poster Session 2

Speaker

Dr Eva Bozsaky (Medical University Vienna, Christian Doppler Lab for Medical Radiation Oncology)

Description

Oral mucositis (OM) is a frequent dose-limiting side effect of radiotherapy of head-and-neck tumours. The pathophysiological basis of the response of the mucosal lining is the radiation-induced impairment of proliferation in the germinal layer of the mucosal epithelium. The contribution of apoptotic processes in both the epithelium and the associated endothelium are currently discussed controversially. Ceramides are essentially involved in apoptotic processes. Therefore, inhibition of ceramide-associated signal transduction was performed to determine the role of apoptosis in an established mouse model of OM. Irradiation was administered as single dose or fractionated treatment with 5x3 Gy/week over 1 week (days 0-4) or 2 weeks (d 0-4 and 7-11), each followed by graded test doses (d 7 or 12, respectively). Single dose or test irradiations were performed with graded doses (5 dose levels, 10 animals) in order to generate complete dose effect curves. Mucosal ulceration, corresponding to confluent mucositis grade 3 of the RTOG/EORTC classification, was analysed as the clinically relevant endpoint. Two ceramide inhibitors were tested: Desipramin, an acidic sphingomyelinase inhibitor, and Fumonisin B1, a ceramide synthase inhibitor. In combination with single dose irradiation, the drugs were administered from day -3 until first diagnosis of ulcer (D) or healing (H) of all ulcers. During 1 week of fractionation, mice were treated from day -3 until day 7, D, or H. During 2 weeks of fractionation, the drugs were applied from day -3 to day 7, 14, D or H, or only during the second week of fractionated irradiation (from d 7 to d 14). In combination with single dose and one week fractionated irradiation, neither Desipramin nor Fumonisin B1 had any significant effect on OM. In combination with fractionation over 2 weeks, treatment with Desipramin showed a significant increase of ED50 value only when administered over the longest time-period (i.e. from d -3 to H). Fumonisin B1 reduced the incidence of mucosal ulcerations in all application protocol during 2 weeks of fractionation with marginal significance. Our results indicate that inhibition of ceramide synthesis via two different pathways influenced the radiation response of oral mucosa only at certain administration protocols, which were associated with “repopulation” processes in the tissue. The findings indicate that apoptosis does not play a predominant role in the pathophysiology of radiation-induced OM.