PNA, NITROXIDE AND 60HDA FOR METASTATIC NEUROBLASTOMA

尽管有目前的治疗方法，转移性神经母细胞瘤的预后 仍然令人沮丧。一种治疗这种肿瘤的实验性化疗药物 是一种细胞毒性神经递质类似物6-羟基多巴胺(6OHDA)。 这种化合物，产生细胞溶解的氧自由基，并且是 优先被肿瘤吸收；但可以预见的是，有 显著的全身性60HDA毒性。试图限制系统性的 毒性，6OHDA已经与抗氧化剂一起进行了测试 氮氧化物化合物坦普尔；这大大提高了治疗 指数为60HDA。然而，坦波尔在体内的半衰期很短，使 有必要将临时波尔的剂量控制在 坦波尔毒性。目前的第一阶段提案集中在一部小说上 化合物，多氮氧基白蛋白(PNA)，可降低坦普尔的毒性 通过延长坦普尔在体内的活性半衰期，并允许 要使用较低的临时醇剂量。(该项目将测试三个- 6OHDA、Tempol和PNA在小鼠模型中的组成系统 神经母细胞瘤。具体目的是确定PNA是否可以安全地 维持TEMPOL水平以限制全身60HDA毒性， 同时让60OHDA有效地杀死肿瘤细胞。基于一个 成功的第一阶段项目，第二阶段将包括进展到 临床试验。 建议的商业应用： 如果成功，这项研究计划将改善医疗水平。 转移性神经母细胞瘤的治疗。改善结果的能力 在这种儿童时期，疾病将为人类和健康提供重要的 护理的好处，并代表着一个重要的商业机会。

Despite current therapies, the prognosis in metastatic neuroblastoma remains dismal. An experimental chemotherapeutic agent for this tumor is the cytotoxic neurotransmitter analog 6-hydroxyl-dopamine (6OHDA). This compound, generates cytolytic oxygen radicals, and is preferentially taken up by the tumor; predictably, though, there is significant systemic 6OHDA toxicity. In an attempt to limit systemic toxicity, 6OHDA has been tested in conjunction with the antioxidant nitroxide compound TEMPOL; this substantially improves the therapeutic index of 6OHDA. However, TEMPOL has a short half-life in vivo, making it necessary to administer TEMPOL dosages approaching the level of TEMPOL toxicity. The present Phase I proposal focuses on a novel compound, polynitroxyl albumin (PNA), which can reduce TEMPOL toxicity by prolonging the active half-life of TEMPOL in vivo and allowing lower TEMPOL dosages to be used. (The project will test the three- component System of 6OHDA, TEMPOL, and PNA in a mouse model of neuroblastoma. The specific aim is to determine whether PNA can safely maintain TEMPOL levels capable of limiting systemic 6OHDA toxicity, while allowing 6OHDA to kill tumor cells efficiently. Based on a successful Phase I project, Phase II will involve progression to a clinical trial. PROPOSED COMMERCIAL APPLICATIONS: If successful this research program will result in improved medical treatment of metastatic neuroblastoma. The ability to improve outcomes in this childhood disease would provide important human and health care benefits and represent a significant commercial opportunity.