Radioprotection by use of Topical Lithium Formulations

描述(申请人提供)：每年约有50万名癌症患者接受放射治疗。放射治疗的急性和晚期后遗症对癌症幸存者的生活质量有负面影响。这些后遗症包括直肠炎、膀胱炎、食道狭窄、皮肤纤维化等。我们提出了一种新的方法来预防对这些患者正常组织的急性和晚期放射损伤。GSK-32途径的抑制剂可以作为辐射防护剂。锂可以抑制GSK-32途径。含锂的局部配方是有效的辐射防护剂，它将金属离子输送到表皮的基础细胞层(祖细胞)，防止放射治疗覆盖的皮肤区域的正常细胞因放射诱导的细胞凋亡。总共12种原型配方将在辐射损伤猪模型中进行筛选。其中六种配方将含有琥珀酸锂，另外六种将含有乳酸锂。将筛选两种水平的锂盐(1%和10%)，分别作为软膏、凝胶和乳剂(乳膏)。最佳配方(S)将基于对提高细胞活力的蛋白质的诱导和对辐射诱导的细胞凋亡的抑制来选择。选定配方的有效性和安全性将在第二阶段得到优化，支持人体试验的概念验证，并向FDA提交IND。 公共卫生相关性：每年有超过50万癌症患者接受放射治疗，目前美国有1000万癌症幸存者。放射治疗的急性和晚期后遗症对癌症幸存者的生活质量有负面影响。这项建议的目标是通过开发一种局部药物来减轻皮肤损伤，这种药物在接受放射治疗之前给正在接受放射治疗的深层肿瘤靶向治疗的癌症患者时，显著提高表皮的活性。

DESCRIPTION (provided by applicant): Roughly 500,000 cancer patients are treated with radiotherapy each year. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. These sequelae include proctitis, cystitis, esophageal stricture, cutaneous fibrosis plus others. We propose a novel means of preventing the acute and late radiation injury to normal tissues in these patients. Inhibitors of GSK-32 pathway can serve as radiation protective agents. Lithium can inhibit the GSK-32 pathway. Lithium-containing topical formulations are candidates for being effective radioprotectors by delivering the metal ion to the basal cell layer of epidermis (progenitor cells), preventing radio-induced apoptosis in normal cells in the skin overlying areas of radiation treatment. A total 12 prototype formulations will be screened in a radiation-induced injury porcine model. Six of the formulations will contain lithium succinate and the other six will contain lithium lactate. Two levels of the lithium salts will be screened (1% and 10%), each as an ointment, a gel, and an emulsion (cream). The best formulation(s) will be selected based on induction of proteins that enhance cell viability and inhibition of radiation-induced apoptosis. The efficacy and safety of selected formulations will be optimized in Phase II, supporting proof-of-concept for testing in humans and an IND submission to the FDA. PUBLIC HEALTH RELEVANCE: Over 500,000 cancer patients are treated with radiotherapy each year, and there are presently 10,000,000 cancer survivors in the US. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. The goal of this proposal is to attenuate skin injury through development of a topical drug that markedly enhances the viability of the epidermis when administered before irradiation therapy to cancer patients undergoing targeted treatment of deeper tumors with radiation therapy.