Therapeutic/Toxic Effects of Electron Emitting Nuclides

描述（由申请方提供）：拟议研究的目的是测量医用放射性核素衰变产生的放射生物学效应的幅度并了解其机制。这些包括通过电子捕获和同质异能跃迁衰变的诊断核素（例如99 mTc，111 In，123 I），以及通过俄歇电子和α粒子发射衰变的有希望的治疗核素（例如123 I，125 I，211 At，213 Bi）。具体而言，我们打算（i）使用计算建模方法来检查用这些放射性核素标记的分子与其靶点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）探讨DNA损伤背后的生物物理过程（裸露到更高阶），并阐明这些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点、细胞类型和细胞放射敏感性相关联，（iv）研究诱导抑制性（125 I）和刺激性（123 I）旁观者效应的因素和机制，（V）量化癌症诱导的上调-用非杀细胞剂量和杀细胞剂量体内照射的小鼠肺细胞以及旁观者小鼠肺细胞中的相关基因表达，和（vi）确定所选放射性标记分子在荷瘤动物中的治疗功效。

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.