THERAPEUTIC/TOXIC EFFECTS OF ELECTRON EMITTING NUCLIDES

拟议研究的目的是了解影响 诊断和治疗发射的密集电离辐射 放射性核素（俄歇电子和α粒子） 保护和癌症治疗。我们计划 阐明辐射 这些短程，高LET粒子的生物物理学，并使用 各种放射生物学效应研究中的信息， 实验治疗学 为此，我们建议研究 损伤的微观分布， 简单的系统（如寡核苷酸，质粒），以响应空间 衰变核素的定位和周围环境的变化 环境 此外，我们将利用单个细胞作为测试 用于确定以下之间的定量关系的系统 微观剂量和有害的生物效应，（一）探索 俄歇电子与DNA非共价结合的分子后果 发射由DNA链断裂表示的放射性卤化物;和（ii） 确定诊断试剂的放射毒性和致突变作用 放射性核素99 mTC和111 In，当它们被细胞浓缩时， 将结果与其转化的微观分布相关联 电子。 研究将在自由基存在下重复进行。 清除剂，以探讨羟基自由基在这些 流程. 此外，我们计划继续进行细胞毒性诱变研究， 以及α粒子衰变后的细胞转化 发射体211 At和212 Bi当位于细胞外时，在等离子体上 膜和核内。 我们还将利用动物肿瘤模型 作为临床前系统，用于确定这些药物在 治疗和建立初步的时间-剂量关系。 这些 模型将包括封闭系统（脑、脊髓、腹膜）， 引进放射性药物和一个系统， 差异灌注（肝脏）。 最后，为了扩大 利用放射性核素粒子治疗，我们计划启动联合 光子加α粒子或俄歇电子模态实验 发射器。

The objective of the proposed research is to understand the implications of densely ionizing radiations emitted by diagnostic and therapeutic radionuclides (Auger electrons and alpha particles) for both radiation protection and cancer therapy. We plan to elucidate the radiation biophysics of these short-range, high-LET particles and to use the information in studies of various radiobiologic effects and in experimental therapeutics. To this end, we propose to examine the microscopic distribution of damage in well-characterized and relatively simple systems (e.g. oligonucleotides, plasmids) in response to spatial positioning of the decaying nuclide and to changes in the surrounding environment. In addition, we will utilize individual cells as test systems for determining the quantitative relationships between microscopic dose and detrimental biologic effects by (i) exploring the molecular consequences of noncovalent DNA binding of Auger-electron emitting radiohalides as expressed by DNA strand breaks; and (ii) determining the radiotoxicity and mutagenic effects of the diagnostic radionuclides 99mTC and 111In when they are concentrated by cells and relating the results to the microscopic distribution of their conversion electrons. Studies will be repeated in the presence of radical scavengers to explore the role of hydroxyl radicals in these processes. In addition, we plan to continue our studies of cytotoxicity mutagenesis, and cellular transformation following the decay of the alpha particle emitters 211At and 212Bi when localized extra-cellularly, on plasma membranes, and intranuclearly. We will also exploit animal tumor models as pre-clinical systems for determining the utility of these agents in therapy and for establishing preliminary time-dose relationships. These models will include closed systems (brain, spinal cord, peritoneum) for the introduction of radiopharmaceuticals and one system accessible by differential perfusion (liver). Finally, in an attempt to extend the utility of radionuclide particle therapy, we plan to initiate combined modality experiments with photons plus alpha particle or Auger electron emitters.