Exploiting multidrug resistance mechanisms to counter radiation toxicity

项目总结/摘要 电离辐射（IR）的意外暴露是一个明确的和目前的风险，由于不可预测的自然 核电站附近的灾难和全球恐怖活动加剧，以及 医疗放射错误和机器故障。目前尚无有效的治疗方法 在放射性事件中潜在的数千名受害者。理想的治疗方法是 可在暴露后至少24小时以丸剂或注射剂形式给药。的主要障碍 设计这样的药物是缺乏一个分子途径，以具体目标。最近的一 小分子文库高通量筛选（HTS）发现项目发现了一个家族， 具有硝基苯磺酰胺（Nitrobenzylsulfonamide，NPH）核的有前途的放射性引发剂。可惜他们的 减轻辐射毒性的作用机制尚不清楚。在一次不相关的 研究了谷胱甘肽（GSH）通过多药耐药转运（MRT）从辐射细胞中流出， 已经认识到MRT的抑制剂共享在筛选的化合物中发现的化学结构。 辐射抑制剂。因为GSH和GSH结合分子的主动外排是一个关键因素， 细胞死亡的决定因素，一个新的想法出现了连接一个研究与其他。假设是 在该提议中测试的是，在IR后抑制MRT介导的GSH流出将拯救细胞免于 死亡，减轻急性辐射毒性。所述放射性激动剂药物选自HTS和 已知的MRT抑制剂将用于研究以下具体目的：1）确定以下的重要性： IR后GSH流出和细胞死亡动力学，2）建立MRT作为IR诱导的细胞死亡的介质， 作为缓解的目标，3）优化GSH外排/MRT抑制剂的给药24小时或更长时间后， 照射，和4）确定GSH流出/MRT抑制剂对造血的不同作用 和胃肠道组织，以减轻器官特异性辐射综合征。的 里程碑将是确定MRT介导的GSH外排与辐射诱导的 死亡，发现一套独特的组织特异性靶点，以减轻急性辐射毒性， 建立一个基础，以开发可获得的药品，在灾难期间广泛分发， 放射性事件

PROJECT SUMMARY/ABSTRACT Unanticipated exposure to ionizing radiation (IR) is a clear and present risk due to unpredictable natural catastrophes near nuclear power plants and heightened global terrorist activities, as well as to medical radiological errors and machine malfunctions. Currently, no effective method exits to treat the potentially thousands of victims during a radiological event. The ideal treatment would be one that could be administered at least 24 hrs after exposure as a pill or injectable. A major obstacle to designing such a pharmaceutical is the lack of a molecular pathway to specifically target. A recent high-throughput screening (HTS) discovery project of small-molecule libraries uncovered a family of promising radiomitigators possessing a nitrophenylsulfonamide (NPS) core. Unfortunately, their mechanism of action in mitigating radiation toxicity is unknown. Serendipitously during an unrelated study on glutathione (GSH) efflux from irradiated cells via multidrug resistance transport (MRT), it was realized that inhibitors of MRT share the NPS chemical structure found in the screened radiomitigators. Because active efflux of GSH and GSH-conjugated molecules is a critical determinant of cell death, a novel idea arose connecting one study with the other. The hypothesis to be tested in this proposal is that inhibition of MRT mediated GSH efflux following IR will rescue cells from death, mitigating acute radiation toxicity. The radiomitigating NPS drugs selected from the HTS and known MRT inhibitors will be used to investigate the following specific aims: 1) Establish importance of GSH efflux and cell death kinetics post-IR, 2) Establish MRT as a mediator of IR-induced cell death and as a target for mitigation, 3) Optimize administration of GSH efflux/MRT inhibitor 24h or more after irradiation, and 4) determine differential effects of GSH efflux/MRT inhibitors on hematopoietic and gastrointestinal tissues to target mitigation of organ-specific radiation syndromes. The milestones will be the identification of a link between MRT-mediated GSH efflux and radiation-induced death, discovery of a set of unique tissue-specific targets for mitigating acute radiation toxicity, and establishment of a basis to develop accessible pharmaceuticals for wide dispersal during a catastrophic radiological event.