PNA, NITROXIDE AND 60HDA FOR METASTATIC NEUROBLASTOMA

尽管目前的治疗，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学治疗剂 是细胞毒性神经递质类似物6-羟基多巴胺（6 OHDA）。 该化合物产生溶细胞氧自由基， 优先被肿瘤吸收;可以预见的是，虽然， 显著的全身性6 OHDA毒性。为了限制系统性 毒性，6 OHDA已与抗氧化剂一起测试 氮氧化合物TEMPOL;这大大提高了治疗效果， 6 OHDA指数。然而，TEMPOL在体内的半衰期很短， 有必要给予TEMPOL剂量接近 TEMPO毒性。目前的第一阶段建议集中在一本小说 化合物，多硝酰基白蛋白（PNA），可降低TEMPOL毒性 通过延长TEMPOL在体内的活性半衰期， 使用较低的TEMPOL剂量。(The项目将测试三个- 6 OHDA、TEMPOL和PNA组成的系统， 神经母细胞瘤具体目的是确定PNA是否可以安全地 维持能够限制全身性6 OHDA毒性的TEMPOL水平， 同时允许6 OHDA有效地杀死肿瘤细胞。基于 成功的第一阶段项目，第二阶段将涉及进展到一个 临床试验 拟议的商业应用： 如果这项研究计划成功， 转移性神经母细胞瘤的治疗。改善结果的能力 在这种儿童疾病中， 这是一个巨大的商业机会，也是一个巨大的商业机会。

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.