Therapeutic/Toxic Effects of Electron Emitting Nuclides

描述（由申请人提供）：拟议研究的目的是测量医学上有用的放射性核素衰变产生的放射生物学效应的大小并了解其潜在机制。这些包括通过电子捕获和异构体跃迁衰变的诊断核素（例如99mTc， 111In, 123I），以及通过俄格电子和α粒子发射衰变的有希望的治疗核素（例如123I， 125I, 211At, 213Bi）。具体而言，我们打算(i)使用计算建模方法来检查这些放射性核素标记的分子与其靶标之间相互作用的性质，从而开发更合理的方法来合成用于癌症治疗的放射性标记分子；（ii）探索这些放射性核素衰变引起的DNA损伤（从裸到高阶）的生物物理过程，并阐明这些是直接或间接机制的结果。（iii）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及其衰变部位、细胞类型和细胞放射敏感性联系起来；（iv）研究诱发抑制性（125I）和刺激性（123I）旁观者效应的因素和机制；(v)量化非杀伤和杀伤剂量小鼠肺细胞以及旁观者小鼠肺细胞中癌症诱导相关基因表达的上调，（vi）确定选定的放射性标记分子在荷瘤动物中的治疗效果。

DESCRIPTION (provided by applicant): The objective of the proposed research is to measure the magnitude of and to understand the mechanisms underlying the radiobiologic effects produced by the decay of medically useful radionuclides. These include diagnostic nuclides that decay by electron capture and isomeric transition (e.g. 99mTc, 111In, 123I), and promising therapeutic ones that decay by Auger-electron and alpha-particle emission (e.g. 123I, 125I, 211At, 213Bi). Specifically, we intend to (i) use computational modeling methods to examine the nature of the interactions between molecules labeled with these radionuclides and their targets, thereby developing more rational approaches to the synthesis of radiolabeled molecules for cancer therapy, (ii) explore the biophysical processes underlying damage to DNA (naked to higher order) caused by the decay of these radionuclides and elucidate whether these are a consequence of direct or indirect mechanisms, (iii) associate radionuclide- decay-induced apoptosis with the physical decay characteristics of these radionuclides and their site of decay, cell type, and cell radiosensitivity, (iv) investigate the factors and mechanisms underlying the induction of inhibitory (125I) and stimulatory (123I) bystander effects, (v) quantify the upregulation of cancer-induction-related gene expression in mouse lung cells irradiated in vivo with noncytocidal and cytocidal doses as well as in bystander mouse lung cells, and (vi) establish the therapeutic efficacy of selected radiolabeled molecules in tumor-bearing animals. PUBLIC HEALTH RELEVANCE The relationship between the intracellular localization of low-energy electron- and alpha-particle- emitting radionuclides and the biologic consequences of the resulting microdistribution of energy has practical considerations for both defining the risks associated with the use of radionuclides in nuclear medicine and assessing the potential of such radionuclides for cancer therapy. We envisage that the multidisciplinary approach proposed in this project (i.e. use of computational modeling methods to predict the nature of interactions between the radiolabeled molecules and DNA, exploration of the biophysical processes responsible for DNA damage, identification of the pathways mediating cell death and the bystander effect, and quantification of the alterations in cancer-induction genes) will help to determine many of the factors underlying the radiobiologic effects of these radionuclides and, thereby, to assess possible detrimental effects.