D-Methionine for the treatment of Oral Mucositis

描述(申请人提供)：粘膜炎，也称为口腔炎，是一种口腔、喉咙或胃肠道衬里的虚弱炎症和溃烂，通常与癌症的放疗或化疗有关。在许多情况下，粘膜炎可能会非常痛苦，使患者无法正常进食，并干扰吞咽、饮水和说话。这些症状通常会因口干症而加剧，口干症是一种唾液分泌严重减少的情况，导致口腔干燥，并伴有不适、说话困难和吞咽困难。在美国，接受抗癌治疗的患者中有20%-40%会出现不同程度的粘膜炎，可能需要降低治疗计划，从而影响治疗。 在目前的提案中，我们将在特定目标1中研究D-蛋氨酸作为治疗分子的用途，以保护细胞(如上皮细胞)免受化疗和/或放射治疗引起的细胞毒性。在这些体外研究之后，将进行特定目标2和3的体内实验。特定目标2的体内研究将使用小鼠嘴唇红斑试验来验证D-蛋氨酸通过保护正常细胞免受放射和/或化疗的细胞毒性，防止嘴唇红斑的发生的假设，这是一种人类粘膜炎的模型。进一步的活体研究将在特定的目标3使用由斯蒂芬·索尼斯博士开发的急性辐射仓鼠模型来完成，索尼斯博士是这项提议的顾问。开发一种药物，如D-蛋氨酸，在不显著改变这些治疗的抗癌效果的情况下，保护正常组织免受放化疗的细胞毒性影响，将显著提高接受癌症治疗的患者的生活质量。这也可能允许对癌症患者进行剂量治疗，而以前由于剂量限制毒性而无法实现。

DESCRIPTION (provided by applicant): Mucositis, also called stomatitis, is a debilitating inflammation and ulceration of the lining of the mouth, throat or gastrointestinal tract most commonly associated with radiotherapy or chemotherapy for cancer. In many cases, mucositis can be extremely painful, preventing the patient from eating normally and interfering with swallowing, drinking and speaking. These symptoms are often exasperated by Xerostomia a condition wherein the production of saliva is severely decreased and results in a dry mouth with discomfort, difficulty in speech and swallowing. In the U.S., 20-40 percent of patients undergoing anticancer therapy will develop mucositis to varying degrees and may require de-escalation of the treatment plan thus compromising therapy. In the present proposal we will investigate in Specific Aim 1, the use of D-Methionine as a therapeutic molecule for protecting cells (e.g. epithelial cells) from cytotoxicity induced by chemo- and/or radiation therapy. These in vitro studies will be followed by in vivo experiments in Specific Aims 2 and 3. In vivo studies in Specific Aim 2 will be accomplished using the mouse lip erythema assay to test the hypothesis that D-Methionine, by protecting normal cells from the cytotoxicity of radiation and/or chemo-therapy, prevents the occurrence of lip erythema, a model for human mucositis. Further in vivo studies will be accomplished in Specific Aim 3 using the acute radiation hamster model developed by Dr. Stephen Sonis, a consultant on this proposal. The development of an agent such as D-Methionine that protects normal tissue from the cytotoxic effects of radio- and chemo-therapy without significantly altering the anticancer efficacy of these therapies would significantly enhance the quality of life of patients undergoing cancer therapy. This may also permit the administration of doses of therapy to cancer patients that were previously unachievable due to dose limiting toxicities.