PNA, NITROXIDE AND 60HDA FOR METASTATIC NEUROBLASTOMA

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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.