Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

摘要 口腔粘膜炎是一种令人痛苦的炎症性疾病，常发生在癌症期间。 这种疗法在美国影响了50万人。伴随的疼痛是如此严重，以至于患者经常 需要麻醉性止痛药。临床表现为口腔和胃肠道溃疡， 机会性感染会加剧这种情况。许多患者还患有口干，造成困难。 吞咽中由于唾液腺功能下降。因此，这些患者经常需要喂食。 中断他们癌症治疗的管子。病人的经济负担令人震惊地高得令人震惊 每名患者额外支付17,000至40,000美元。因此，预防口腔粘膜炎将大大增强 癌症治疗以及患者的健康。GlycoMira的领先候选者GM-0111是一种新的 消炎药。SBIR I期研究结果显示其在 放射性口腔粘膜炎动物模型的建立：GM-0111可减少放射性口腔黏膜溃疡和炎症反应 舌头。组织学上，GM-0111治疗组的舌组织渗出明显减少。 粘膜层较厚的白细胞与组织相比防止粘液腺病变 从车辆处理过的动物身上。生化分析也显示白细胞酶MPO持续降低 GM-0111治疗组神经生长因子(NGF)活性降低。在……里面 此外，GM-0111治疗可防止辐射引起的唾液腺变化。总体而言，数据 提示GM-0111预防口腔粘膜炎是可行的。目前SBIR第二阶段的应用 建议进一步开发GM-0111作为一种可行和有效的口腔粘膜炎治疗方法。目标是 (1)研究放射性口腔粘膜炎动物模型的最佳给药方案，(2)确定 GM-0111口腔黏膜局部给药的最佳处方：(3)GM-0111口腔黏膜局部给药的验证 辐射和化学辐射诱导的动物模型中的分子靶点研究 减少口腔粘膜炎的GM-0111。拟议的研究结果将导致交付一个可行的 以及对患有这种毁灭性疾病的患者进行有效的治疗。

ABSTRACT Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million people in the US. The accompanying pain is so severe that patients often require narcotic pain medicines. The clinical manifestations are ulcers in the mouth and gastrointestinal tract, which are exacerbated by opportunistic infections. Many patients also suffer from dry mouth causing difficulty in swallowing because of the decreased salivary gland function. As a result, these patients often need feeding tubes which interrupts their cancer treatment. The financial burden to the patient is staggeringly high costing an additional $17,000 to $40,000 for each patient. Preventing oral mucositis will therefore greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-0111, is a new class of anti-inflammatory drugs. The SBIR Phase I study results demonstrate its powerful anti-inflammatory effects in a radiation-induced oral mucositis animal model: GM-0111 reduced tissue ulceration and inflammation in the tongue. Histologically, tongue tissues from the GM-0111 treated group showed markedly reduced infiltration of leukocytes with thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated animals. Biochemical analyses also showed consistently lower leukocyte enzyme MPO activity as well as reduced concentration of nerve growth factor (NGF) in GM-0111 treatment groups. In addition, GM-0111 treatment prevented radiation-induced alterations of the salivary glands. Overall, the data suggest that it is feasible to use GM-0111 to prevent oral mucositis. The current SBIR Phase II application proposes to further develop GM-0111 as a viable and effective therapy for oral mucositis. The objectives are to (1) investigate the optimal dosing regimen in a radiation-induced oral mucositis animal model, (2) determine the optimal formulation for topical delivery of GM-0111 in the oral mucosa, (3) validate the topical GM-0111 formulation in radiation and chemoradiation-induced animal models, and (4) investigate the molecular targets of GM-0111 to reduce oral mucositis. The results of the proposed research will lead to the delivery of a viable and effective therapy to the patients suffering from this devastating disease.