Toshkov Ilia A, Gleiberman Anatoli S, Mett Vadim L, Hutson Alan D, Singh Anurag K, Gudkov Andrei V, Burdelya Lyudmila G
a Buffalo BioLabs, LLC, Buffalo, New York.
b Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York.
Radiat Res. 2017 May;187(5):570-580. doi: 10.1667/RR14514.1. Epub 2017 Mar 21.
Radiation treatment of head and neck cancer frequently causes severe collateral damage to normal tissues including mouth mucosa, salivary glands and skin. This toxicity limits the radiation dose that can be delivered and affects the patient's quality of life. Previous studies in mice and nonhuman primates showed that entolimod, a toll-like receptor 5 (TLR5) agonist derived from bacterial flagellin, effectively reduced radiation damage to hematopoietic and gastrointestinal tissues in both total-body and local irradiation scenarios, with no protection of tumors. Here, using a mouse model, we analyzed the efficacy of entolimod administered before or after irradiation in reducing damage to normal tissues. Animals received local fractionated radiation to the head and neck area, thus modeling radiotherapy of head and neck cancer. Tissue damage was evaluated through histomorphological examination of samples collected at different time points up to four weeks, mice were exposed locally to five daily fractions of 5, 6 or 7 Gy. A semiquantitative scoring system was used to assess the severity of observed pathomorphological changes. In this model, radiation damage was most severe in the lips, tongue and skin, moderate in the upper esophagus and minor in salivary glands. The kinetics of injury appearance and recovery of normal morphology varied among tissues, with maximal damage to the tongue, esophagus and salivary glands developing at earlier times (days 8-11 postirradiation) relative to that of lip and skin mucosa (days 11-15 postirradiation). While both tested regimens of entolimod significantly reduced the extent of radiation damage and accelerated restoration of normal structure in all tissues analyzed, administration of entolimod 1 h after each irradiation was more effective than treatment 30 min before irradiation. These results support the potential clinical use of entolimod as an adjuvant for improving the therapeutic index of head and neck cancer radiotherapy by reducing the radiation toxicity in normal tissues.
头颈部癌的放射治疗常常会对包括口腔黏膜、唾液腺和皮肤在内的正常组织造成严重的附带损伤。这种毒性限制了可给予的放射剂量，并影响患者的生活质量。先前在小鼠和非人类灵长类动物中的研究表明，恩托利莫德是一种源自细菌鞭毛蛋白的Toll样受体5（TLR5）激动剂，在全身照射和局部照射情况下均能有效减少对造血组织和胃肠道组织的放射损伤，且对肿瘤无保护作用。在此，我们使用小鼠模型分析了在照射前或照射后给予恩托利莫德在减少对正常组织损伤方面的疗效。动物接受对头颈部区域的局部分次放射，以此模拟头颈部癌的放射治疗。通过对在长达四周的不同时间点采集的样本进行组织形态学检查来评估组织损伤，小鼠局部接受每天5次、每次5、6或7 Gy的照射。使用半定量评分系统评估观察到的病理形态学变化的严重程度。在该模型中，放射损伤在嘴唇、舌头和皮肤中最为严重，在上段食管中为中度，在唾液腺中较轻。正常形态的损伤出现和恢复的动力学在不同组织中有所不同，相对于嘴唇和皮肤黏膜（照射后第11 - 15天），舌头、食管和唾液腺的最大损伤在较早时间（照射后第8 - 11天）出现。虽然两种测试的恩托利莫德给药方案均显著降低了所有分析组织中的放射损伤程度并加速了正常结构的恢复，但每次照射后1小时给予恩托利莫德比照射前30分钟治疗更有效。这些结果支持恩托利莫德作为一种佐剂的潜在临床应用，通过降低正常组织中的放射毒性来提高头颈部癌放射治疗的治疗指数。
