OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

该项目的目标是开发能够重金属螯合剂， 金属去除和减少放射性核素毒性的口服 这些螯合剂的应用。 目前，职业暴露 个体用二亚乙基三胺的Ca-和Zn-螯合物治疗， 五乙酸（DTPA）。 DTPA形成具有高稳定性的螯合物， 强亲水性，需要胃肠外给药， 排泄 在这个项目的前两年，我们设计了， 合成并测试了几类新的螯合化合物。 来自 体外试验，几种二亚乙基三胺-（DT）和三亚乙基四胺- (TT)的化合物进行了鉴定和体内测试。 口服给药时 它们在去除大鼠体内的老化的241 Am沉积物方面非常有效。 Am是 用作5 f轨道要素的模型。 具体而言，我们建议：1） 继续体内试验，以确定DT和TT的剂量和时间效应- 基于螯合剂的Am和Pu去除。 将测定排泄率， 用中子诱导的方法获得钚的组织定位模式 放射自显影 其他类别的聚氨基羧酸将进行测试 在体外试验成功后。 2)确定的效率 DT-和TT-基螯合剂对除 锕系元素。 这些螯合物将结合铅和铁，初步研究将在 铅是一种重要的环境和职业毒素。 3)具有改善靶器官的螯合物的开发、合成和检测 的特异性 为此，化学部分，一些类似于内源性 底物，将连接到聚氨基羧酸。 这可能 提供了相当大的治疗优势。 4)为了确定器官和 口服螯合剂的组织分布。 选择放射性标记 将合成螯合物，并使用 生物化学和放射自显影方法。 5)为了确定 长期（>6年）螯合治疗（DTPA）对犬的影响。 我们 从另一项研究中获得了动物的完整骨骼， 使用静态和动态组织形态测量确定骨骼变化 方法. 这将提供一些独特的和实用的信息， 长期螯合治疗。 这些研究应有助于发展 可显著改善治疗方法的新螯合剂 用于减少来自锕系元素、镧系元素和可能的其他元素的毒性， 金属.

The goal of this project is to develop chelating agents capable of heavy metal decorporation and to reduce radionuclide toxicity by the oral application of these chelators. At present, occupationally exposed individuals are treated with Ca- and Zn-chelates of diethylenetriamine- pentaacetic acid (DTPA). DTPA forms chelates with high stability but is strongly hydrophilic, requires parenteral administration and is rapidly excreted. In the first 2 years of this project, we have designed, synthesized and tested several classes of new chelation compounds. From in vitro testing, several diethylenetriamine-(DT) and triethylenetetramine- (TT) based compounds were identified and tested in vivo. When given orally they are very effective in removing aged 241Am deposits in rats. Am is used as a model of 5f-orbital elements. Specifically we propose to: 1) Continue in vivo testing to determine dose and time effects of DT and TT- based chelons on Am and Pu removal. Excretion rates will be determined and tissue localization patterns of Pu will be obtained by neutron-induced autoradiography. Other classes of polyaminocarboxylic acids will be tested following successful in vitro testing. 2) To determine the efficiency of DT- and TT-based chelons on the decorporation of metals other than actinides. These chelons will bind Pb and Fe and initial studies will be done with Pb, which is a significant environmental and occupational toxin. 3) To develop, synthesize and test chelons with improve target organ specificity. For this, chemical moieties, some analogous to endogenous substrates, will be attached to the polyaminocarboxylic acids. This may offer considerable therapeutic advantage. 4) To determine the organ and tissue distribution of orally administered chelons. Select radiolabeled chelons will be synthesized and their distribution determined using biochemical and autoradiographic methods. 5) To determine the skeletal effects of long term (>6 years) chelation treatment (DTPA) in dogs. We obtained complete skeletons from animals involved in another study and will determine skeletal changes using static and dynamic histomorphometric methods. This will provide some unique and practical information on long term chelation therapy. These studies should lead to the development of new chelation agents that may substantially improve therapeutic approaches for the reduction of toxicity from actinide, lanthanide and perhaps other metals.