Ferritin is an iron-storage protein that is found in normal human serum. Greater than normal serum levels are found in some patients with neuroblastoma and predict a poor outcome. Indirect evidence suggests that ferritin in these patients may be synthesized by their tumor cells. In an attempt to understand why ferritin levels correlate with prognosis, studies have focused on the ability of ferritin to inhibit host immune responses and thereby enhance tumor growth. It is postulated that in addition to these effects, ferritin or the ferric ions that it carries may function as a growth factor for neuroblastoma and directly contribute to tumor growth. As a correlary it is postulated that chelation of iron may provide an approach to the treatment of neuroblastoma. Preliminary data suggest that desferoxamine, a high affinity iron chelator which can extract iron from ferritin, kills growing neuroblastoma cells in vitro. To further explore the biological role of ferritin in neuroblastoma as well as the mechanism by which desferoxamine kills neuroblastoma cells, it is proposed: to establish that neuroblastoma cells can synthesize ferritin; to determine whether ferritin potentiates nucleic acid or protein synthesis by neuroblastoma cells in serum-free medium; and to study the ability of neuroblastoma cells to bind ferritin in the manner of known growth factors. In addition the effect of desferoxamine on tumor cell lines with respect to DNA, RNA and protein synthesis, cell cycling, and activity of iron-dependent cellular enzymes will be studied. Finally, utilizing available toxicity data, a phase II clinical trial of desferoxamine in children with end-stage neuroblastoma and other malignancies will be conducted.
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