Therapeutic/Toxic Effects of Electron Emitting Nuclides

拟议研究的目的是阐明密集的 诊断和治疗放射性核素发出的电离辐射(俄歇电子和 阿尔法粒子)，用于辐射防护和癌症治疗。我们打算探索 在具有良好特性的简单系统(质粒)和 高阶染色质结构(哺乳动物细胞核)，并评估 衰变核素的空间定位(通过计算建模方法确定) 以及周围环境的变化。我们还计划确定数量 微观剂量与有害生物效应的关系 放射性核素衰变诱导的细胞凋亡及其物理衰变特征 放射性核素及其衰变部位、细胞类型和细胞辐射敏感性；(Ii)调查 FN活体肿瘤模型中的旁观者效应；(Iii)评估衰变的诱变反应 在细胞质定位后的这些放射性核素，并检查这是否是一个 直接或间接机制的后果；和(4)确定导致 正常哺乳动物细胞中基因表达的变化和肿瘤转化。 最后，我们将开发一个动物肿瘤模型作为临床前系统，以确定其实用性。 胸苷类似物5-[12Sl]碘-2‘-脱氧尿苷在癌症治疗中的应用。

The objective of the proposed research is to elucidate 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 intend to explore mechanisms producing DNA damage in well-characterized simple systems (plasmids) and in higher order chromatin structures (mammalian cell nuclei) and assess the consequence of spatial positioning of the decaying nuclide (ascertained by computational modeling methods) as well as changes in the surrounding environment. We also plan to determine the quantitative relationships between microscopic dose and detrimental biologic effects by (i) associating radionuclide-decay-induced apoptosis with the physical decay characteristics of these radionuclides, their site of decay, cell type, and cell radiosensitivity; (ii) investigating the bystander effect in fn-vivo tumor models; (iii) assessing the mutagenic response to the decay of these radionuclides following cytoplasmic localization and examining whether this is a consequence of direct or indirect mechanisms; and (iv) determining doses that lead to alterations in gene expression and neoplastic transformation in normal mammalian cells. Finally, we will exploit an animal tumor model as a preclinical system for determining the utility of the thymidine analog 5-[12Sl]iodo-2'-deoxyuridine in cancer therapy.