Therapeutic/Toxic Effects of Electron Emitting Nuclides

描述(由申请人提供)：拟议研究的目标是测量具有医学用途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的机制。这些核素包括通过电子俘获和同质异能跃迁而衰变的诊断性核素(例如99mTc、111In、123I)，以及通过俄歇电子和阿尔法粒子发射而衰变的有希望的治疗性核素(例如123I、125I、211At、213Bi)。具体地说，我们打算(I)使用计算模拟方法来检验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的衰变对DNA(从裸露到更高阶)潜在的生物物理过程，并阐明这些过程是直接还是间接机制的结果，(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位置、细胞类型和细胞辐射敏感性联系起来。(Iv)研究抑制性(125I)和刺激性(123I)旁观者效应的诱导因素和机制，(V)量化非细胞杀伤性和细胞杀伤性剂量照射的体内小鼠肺细胞以及旁观者肺细胞中癌症诱导相关基因的表达上调，以及(Vi)确定选定的放射性标记分子在荷瘤动物中的治疗效果。 公共卫生相关性低能电子和阿尔法粒子发射的放射性核素在细胞内的定位与由此产生的能量微观分布的生物后果之间的关系对于确定与在核医学中使用放射性核素相关的风险和评估这种放射性核素用于癌症治疗的潜力都具有实际意义。我们预计，本项目中提出的多学科方法(即使用计算模拟方法来预测放射性标记分子与DNA之间相互作用的性质、探索导致DNA损伤的生物物理过程、确定介导细胞死亡和旁观者效应的途径以及量化致癌基因的变化)将有助于确定这些放射性核素的放射生物效应的许多潜在因素，从而评估可能的有害影响。

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.