THE ROLE OF HUMAN FERRITIN IN THE LOCALIZATION OF GA-67

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The long-term objectives of this project are to understand the localization mechanism of the tumor and abscess localizing radiopharmaceutical, Ga-67, in order to develop strategies to improve its diagnostic efficacy and devise new techniques which may supplant or replace it. The knowledge gained from this project should serve as a model for the rational design of future agents and may provide some insight into tumor physiology. This knowledge may also help to improve the therapeutic efficacy of gallium nitrate (NCI 15200) now in Phase I clinical trials. Specifically, we wish to investigate the role of human ferritin lactoferrin (LF) and transferrin (TF) in nuclide localization. We plan to fully characterize the affinity of these macromolecules for Ga-67 using purified protein preparations and examining varius factors found intracellularly which may modulate this affinity. Of particular importance is understanding the mechanism of action of various phosphate containing compounds, e.g., ATP, which we have previously shown promote in vitro the translocation of nuclide between LF or TF to horse ferritin. With the knowledge gleaned from these experiments, we plan to investigate the role of these proteins in nuclide uptake in human monocytes and macrophages as a model system and how the concentration of cytoplasmic constituents, such as ATP, affect uptake. Lastly, we will explore how other nuclides are bound and translocated in this model system. We shall focus primarily on those nuclides which could replace Ga-67 as an abscess or tumor imaging agent. We hope to apply the HPLC technique to characterize the affinities of these macromolecules under a variety of conditions. If not, standard protein chromatographic procedures will be used. We will use the new Percoll gradient technique, which isolates monocytes and lymphocytes according to their density differences.