Radioprotection by use of Topical Lithium Formulations

描述（由申请人提供）：每年大约有50万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、食管狭窄、皮肤纤维化等。我们提出了一种预防这些患者正常组织急性和晚期辐射损伤的新方法。GSK-32通路抑制剂可作为辐射防护剂。锂可以抑制GSK-32通路。含锂外用制剂可作为有效的辐射保护剂，通过将金属离子输送到表皮基底细胞层（祖细胞），防止辐射治疗覆盖区域皮肤正常细胞的放射性诱导凋亡。共有12种原型制剂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。将筛选两种浓度的锂盐（1%和10%），分别作为软膏、凝胶和乳液（乳霜）。最佳配方将根据诱导增强细胞活力和抑制辐射诱导的细胞凋亡的蛋白质来选择。选定制剂的有效性和安全性将在II期进行优化，支持人体试验的概念验证，并向FDA提交IND。

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.