Therapeutic/Toxic Effects of Electron Emitting Nuclides

描述(申请人提供)：拟议研究的目的是阐明诊断和治疗放射性核素(俄歇电子和阿尔法粒子)发出的高密度电离辐射对辐射防护和癌症治疗的影响。我们打算探索在具有良好特征的简单系统(质粒)和高阶染色质结构(哺乳动物细胞核)中产生DNA损伤的机制，并评估衰变核素的空间定位(通过计算模型方法确定)以及周围环境的变化的后果。我们还计划通过以下方式确定微观剂量和有害生物效应之间的定量关系：(I)将放射性核素衰变诱导的细胞凋亡与这些放射性核素的物理衰变特征、它们的衰变部位、细胞类型和细胞辐射敏感性联系起来；(Ii)研究FN活体肿瘤模型中的旁观者效应；(Iii)评估这些放射性核素在细胞质定位后的衰变的诱变反应，并检查这是否是直接或间接机制的结果；以及(Iv)确定导致正常哺乳动物细胞中基因表达变化和肿瘤转化的剂量。最后，我们将开发一个动物肿瘤模型作为临床前系统，以确定胸苷类似物5-[12Sl]碘-2‘-脱氧尿苷在癌症治疗中的用途。

DESCRIPTION (provided by applicant):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.