Development of an LPA receptor modulator Rx100 as a radioprotectant

开发 LPA 受体调节剂 Rx100 作为辐射防护剂

• 批准号: 7479472
• 负责人: Wenlin Deng
• 金额: $ 10万
• 依托单位: RXBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-27 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479472
• 关键词: Acids; Acute; Agonist; Biological Assay; Bone Marrow; Cancer Patient; Cessation of life; Chemical Structure; Class; Computer Simulation; Conscious; Control Groups; Data; Development; Dose; Dose-Rate; End Point; Event; Exposure to; Gastrointestinal tract structure; Goals; Growth Factor; Hematopoiesis; Hematopoietic; Ionizing radiation; Life; Lysophospholipids; Medical; Methods; Mucous Membrane; Mus; Myelosuppression; Nuclear; Nuclear Accidents; Oral; Pancytopenia; Pharmaceutical Preparations; Phospholipids; Public Health; Radiation; Radiation Syndromes; Radiation induced damage; Radiation therapy; Radiation-Protective Agents; Radioprotection; Rate; Research Design; Route; Schedule; Solid; Source; Subcutaneous Injections; Syndrome; Terrorism; Therapeutic; Treatment Protocols; Week; Whole-Body Irradiation; Work; base; cell type; day; gastrointestinal; irradiation; lysophosphatidic acid; mouse model; prevent; receptor; subcutaneous

DESCRIPTION (provided by applicant): Bone marrow and gastrointestinal mucosa are highly sensitive to radiation exposure. Radiation-induced damage to bone marrow and the gastrointestinal tract could be lethal in events such as nuclear accidents or radiation terrorism, depending on radiation doses, exposure rate and quality. No truly satisfactory radioprotective drugs are yet available. The phospholipids growth factor lsophosphatidic acid (LPA) is a prosurvival factor acting via LPA receptors. We have synthesized a LPA receptor modulator Rx100, a partial agonist for LPA1 & LPA3, and a potent agonist for LAP2 receptor. We have proof of principle that Rx100, when applied either orally or subcutaneously, 1 hr before or 3 hrs after radiation exposure effectively reduced radiation-induced lethality to mice. We propose to fully evaluate Rx100 as a radioprotectant and a radiomitigator. Our ultimate goal is to provide a highly efficient medical countermeasure against radiological and nuclear threats, and a potent radioprotectant for cancer patients. Research design: Evaluate the efficacy of Rx100 in ameliorating radiation-associated hematopoietic syndrome. (1) We will use a mouse model of whole-body radiation; (2) We will optimize dosing schedules by oral and subcutaneous routes; (3) We will compare all data to decide two final schedules: one for Rx100 administered prior to radiation exposure as a radioprotectant and one as a radiomitigator; (4) We will quantify Rx100-initiated radioprotection by dose-reduction factor (DRF). Methods: (1) whole-body radiation of mice. Conscious mice are subjected to whole-body irradiation using a Cs-137 source at a rate of 4.6 Gy/min. (2) Hematopoietic assay. The primary endpoint is 30 days overall survival. For determining DRF, mice will be subjected to graded lethal doses of radiation exposure to generate survival curves for control groups and Rx100-treated groups. DRF will be calculated by probit analysis. PUBLIC HEALTH RELEVANCE: Exposure to radiation could result in fatal damage to bone marrow and the gut. No truly satisfactory radioprotective drugs are available yet. We propose to develop Rx100 into a highly efficient medical countermeasure against radiological and nuclear threats, and a potent radioprotectant for cancer patients.

描述（申请人提供）：骨髓和胃肠道粘膜对辐射高度敏感。在核事故或辐射恐怖主义等事件中，辐射引起的骨髓和胃肠道损伤可能是致命的，这取决于辐射剂量、照射率和质量。目前还没有真正令人满意的辐射防护药物。磷脂生长因子磷脂酸（LPA）是一种通过LPA受体起作用的促生存因子。我们合成了LPA受体调节剂Rx100， LPA1和LPA3的部分激动剂，以及LAP2受体的强效激动剂。我们有原理证明，Rx100在辐射照射前1小时或照射后3小时口服或皮下应用，可有效降低辐射引起的小鼠死亡率。我们建议对Rx100作为辐射防护剂和辐射缓解剂进行全面评估。我们的最终目标是提供一种针对放射性和核威胁的高效医疗对策，并为癌症患者提供一种有效的放射保护剂。研究设计：评价Rx100改善放射相关造血综合征的疗效。(1)我们将使用小鼠全身辐射模型；(2)优化口服和皮下给药方案；(3)我们将比较所有数据以决定两种最终方案：一种是在辐射暴露前将Rx100作为辐射保护剂施用，另一种是作为辐射缓解剂施用；(4)我们将通过剂量减少因子（DRF）量化rx100引发的辐射防护。方法：(1)小鼠全身辐射。有意识的小鼠受到铯-137源以4.6 Gy/min的速率进行全身照射。(2)造血试验。主要终点为30天总生存期。为了确定DRF，小鼠将接受分级致死剂量的辐射暴露，以生成对照组和rx100处理组的生存曲线。DRF将通过概率分析计算。公共卫生相关性：暴露于辐射可导致骨髓和肠道的致命损害。目前还没有真正令人满意的辐射防护药物。我们建议将Rx100发展成为一种针对放射性和核威胁的高效医疗对策，以及癌症患者的强效放射保护剂。