Exploiting multidrug resistance mechanisms to counter radiation toxicity

项目摘要/摘要 由于不可预测的自然因素，意外暴露于电离辐射(IR)是一种明确而现实的风险 核电站附近的灾难和全球恐怖主义活动加剧，以及 医疗放射错误和机器故障。目前尚无有效的治疗方法。 在一次辐射事件中可能会有数千名受害者。理想的治疗方法应该是 可在暴露后至少24小时以药丸或注射的形式给药。一个主要障碍是 设计这样一种药物是缺乏一条特定靶点的分子途径。最近 高通量筛选(HTS)小分子文库发现项目发现了一族 具有硝基苯磺酰胺(NPS)核的有前途的放射增强剂。不幸的是，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 谷胱甘肽(GSH)经多药耐药转运(MRT)外排的研究 实现了MRT抑制剂与筛选的NPS的化学结构相同 放射治疗师。因为GSH和GSH结合分子的主动外流是一个关键 细胞死亡的决定因素，一个新的想法出现了，将一项研究与另一项研究联系起来。假设是 在这项建议中测试的是，抑制MRT介导的GSH外流将使IR后的细胞从 死亡，减轻急性辐射毒性。NPS放射防护药物选自HTS和 已知的MRT抑制剂将用于研究以下具体目标：1)确定 IR后GSH外流和细胞死亡动力学，2)确定MRT是IR诱导的细胞死亡的中介。 作为缓解的目标，3)优化GSH外排/MRT抑制剂24小时或更长时间的给药 以及4)确定GSH外排/MRT抑制剂对造血的不同影响。 和胃肠道组织，以减轻器官特异性辐射综合征。这个 里程碑将是确定MRT介导的GSH外流和辐射诱导之间的联系 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，以及 建立一个基础，以开发可获得的药物，以便在灾难期间广泛传播 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.