AMELIORATION OF ORAL MUCOSITIS IN ANIMAL MODELS

动物模型中口腔粘膜炎的改善

• 批准号: 2774154
• 负责人: JOHN DOUGLAS HALEY
• 金额: $ 23.76万
• 依托单位: OSI PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2774154
• 关键词: biomarker; colony stimulating factor; cytokine; cytotoxicity; disease /disorder model; hamsters; histology; inflammation; medical complication; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; oral mucosa; radioprotective agents; transforming growth factors

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. The oral cavity is a frequently identifiable source of sepsis in the granulocytopenic cancer patient. Transforming growth factors-beta (TGF-betas) have been shown significantly reducing the incidence, severity and duration of oral mucositis in hamsters. In Phase I we developed a robust animal model for radiation and combined chemotherapy/radiation in the Golden Syrian hamster. These models employed a fractionated radiation regimen to induce significant mucositis with little mortality and acceptable weight loss. Histological examination of the oral mucosa showed a similar morphologic appearance and time course when compared to human clinical samples. A series sensitive surrogate markers of tissue damage to evaluate experimental mucositis and its pathophysiological basis were established, including markers of inflammation, markers of epithelial layer water loss, markers of cell stress and cell cycle markers. These marker studies were correlated with the histologic evaluation of the mucosal tissue over a time course following cytotoxic therapy. We propose to assess the dose, schedule and route of administration dependence of TGF-beta3 in the amelioration of radiation-induced mucositis, using the mucositis models and surrogate marker systems developed in Phase I. The medial meed and market potential for an effective agent which prevents or treats oral mucositis is substantial. PROPOSED COMMERCIAL APPLICATION Oral mucositis is a painful and sometimes life-threatening complication observed in 20-40 percent of cancer patients receiving chemo and radio-therapy. The medical need and market potential for an effective therapeutant for this indication are large.

粘膜炎是接受癌症化疗的患者常见的剂量限制性并发症，其源于上皮细胞层的损伤。 口腔是粒细胞减少性癌症患者败血症的常见来源。 转化生长因子-β (TGF-β) 已被证明可显着降低仓鼠口腔粘膜炎的发病率、严重程度和持续时间。在第一阶段，我们在金色叙利亚仓鼠中开发了一种稳健的放疗和联合化疗/放疗动物模型。这些模型采用分次放射治疗来诱发显着的粘膜炎，死亡率极低，体重减轻也可接受。 与人类临床样本相比，口腔粘膜的组织学检查显示出相似的形态学外观和时间进程。 建立了一系列敏感的组织损伤替代标志物来评价实验性粘膜炎及其病理生理基础，包括炎症标志物、上皮层失水标志物、细胞应激标志物和细胞周期标志物。 这些标志物研究与细胞毒治疗后一段时间内粘膜组织的组织学评估相关。我们建议使用 I 期开发的粘膜炎模型和替代标记系统来评估 TGF-β3 在改善放射性粘膜炎中的剂量、时间表和给药途径依赖性。预防或治疗口腔粘膜炎具有重要意义。拟议的商业应用 口腔粘膜炎是一种痛苦的、有时甚至危及生命的并发症，在接受化疗和放疗的癌症患者中观察到有 20-40%。 针对该适应症的有效治疗剂的医疗需求和市场潜力巨大。