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

该项目的长期目标是了解本地化 肿瘤和脓肿定位机制的放射性药物，镓-67， 为了制定策略以提高其诊断效率和 想出新的技术来取代它。《知识》 本工程取得的成果可作为合理设计的样板。 未来的药物，并可能提供一些对肿瘤生理学的洞察。这 知识也可能有助于提高镓的治疗效果 硝酸盐(NCI 15200)目前处于I期临床试验。具体来说，我们希望 人铁蛋白乳铁蛋白(LF)和转铁蛋白的作用 (Tf)核素定位。我们计划全面描述这种亲和力 使用纯化的蛋白质制剂对Ga-67的这些大分子的影响 检查细胞内发现的可能调节这一变化的各种因素 亲和力。尤其重要的是要了解 各种含磷化合物的作用，例如我们有的三磷酸腺苷 先前研究表明，在体外促进核素在Lf之间的转移 或者从转铁蛋白到马铁蛋白。用从这些中收集到的知识 实验中，我们计划研究这些蛋白质在核素中的作用 作为模型系统的人单核细胞和巨噬细胞的摄取以及 细胞质成分的浓度，如三磷酸腺苷，影响吸收。 最后，我们将探索其他核素是如何结合和转移到 这个模型系统。我们将主要集中在那些可能 取代Ga-67作为脓肿或肿瘤显像剂。我们希望应用 高效液相色谱技术表征这些大分子的亲和力 各种条件。如果不是，标准蛋白质层析 将使用程序。我们将使用新的Percoll梯度技术， 它根据单核细胞和淋巴细胞的密度分离它们 不同之处。

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.