Secoisolariciresinol Diglucoside (SDB) Protection in Radiation Pheumonopathy

开环异落叶松树脂醇二葡萄糖苷 (SDB) 对放射性肺病的保护作用

基本信息

批准号：
8103929
负责人：
Melpo Christofidou-Solomidou
金额：
$ 63.15万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8103929
关键词：
3-nitrotyrosine A549 Acute Adrenal Cortex Hormones Adverse effects Affect Alveolar wall Amifostine Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Biological Biological Assay Cancer Patient Cell Death Cells Cereals Chemicals Chemopreventive Agent Chest Clinic Clinical Clinical Trials Collagen Complex DNA DNA Damage Data Deposition Development Diet Dietary Fiber Dietary Formulations Dietary Supplementation Dose Drug Formulations Effectiveness Endothelial Cells Ensure Enzyme Gene Enzymes Epidermal Growth Factor Receptor Exploratory/Developmental Grant for Diagnostic Cancer Imaging Fibrosis Flax Free Radical Scavengers Free Radicals Future Generations Genes Goals Growth Human Immunosuppression In Vitro Inflammation Inflammatory Intestines Ionizing radiation K-ras mouse model Knockout Mice Laboratory Study Lethal Dose 50 Life Lignans Lipids Lung Lung Neoplasms Lung diseases Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Mus Neoplasm Metastasis Neoplasms Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Omega-3 Fatty Acids Oxidative Stress Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Pneumonia Post-Translational Protein Processing Premedication Property Proto-Oncogene Proteins c-akt Pulmonary Fibrosis Pulmonary function tests Radiation Radiation Induced DNA Damage Radiation Injuries Radiation Pneumonitis Radiation Tolerance Radiation Toxicity Radiation therapy Radiologic Finding Radioprotection Radiosensitization Reaction Reactive Oxygen Species Reporter Reporting Response Elements Role Signal Pathway Specificity Staging Structure Structure of parenchyma of lung Superoxide Dismutase Supportive care Syndrome Testing Therapeutic Therapeutic Effect Thoracic Oncology Time Tissues Toxic effect Transcriptional Activation Transgenic Organisms Tumor Tissue Water aminothiol angiogenesis base cancer cell cancer radiation therapy cancer therapy cell injury clinically significant cytotoxic design enzyme therapy flaxseed lignan improved in vivo interstitial irradiation killings lung injury lung volume mouse model neoplastic cell neutrophil novel novel therapeutics prevent protective effect public health relevance response secoisolariciresinol diglucoside transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Usefulness of thoracic radiotherapy is greatly limited by lung sensitivity to irradiation doses necessary to eradicate malignant cells. Clinically significant radiation toxicity occurs in up to 30% of patients irradiated for lung cancer and about 10-15% of other thoracic oncology patients. The need to protect "normal" lung parenchyma from radiation injury compromises delivery of tumoricidal radiotherapy doses. Therefore, radioprotectors that would increase the therapeutic ratio of radiotherapy are urgently needed. Reactive oxygen species induced by ionizing radiation contribute significantly to the pathogenesis of fibrotic lung disease. However the molecular pathways from the oxidative tissue insult to late radiation fibrosis are unclear and at this time, no free radical scavenger offers acceptable levels of pulmonary radioprotection without serious side effects. We and others have shown that antioxidant enzyme therapy alleviates radiation- induced fibrotic lung disease and our preliminary data show that wholegrain flaxseed (FS) or FS lignans, bioactive compounds with known antioxidant, anti-inflammatory and anticarcinogenic properties, induce transcriptional activation of antioxidant enzyme genes in mouse lungs. Furthermore, when evaluated in our mouse model of thoracic radiation-induced pneumonopathy, whole grain FS diet robustly increased mouse survival, abrogated lung fibrosis and decreased oxidative tissue damage while radiosensitizing lung tumor. Therefore, we hypothesize that dietary FS lignan-mediated activation of antioxidant genes may be a novel therapeutic strategy to alleviate radiation pneumonopathy. In the current study, in Aim 1 we will explore the potential pulmonary radioprotective efficacy of FS lignans in a well-established murine model of radiation lung injury using dietary formulations of Secoisolariciresinol Diglucoside (SDG), the main FS lignan precursor. In Aim 2 we will determine if ARE activation is implicated in the mechanism of protection and establish their cell specificity of action. In Aim 3 we will evaluate lignan-mediated radiosensitization of lung cancer cells using a novel K-ras mouse model of orthotopic lung cancer. Successful completion of the proposed studies will elucidate the mechanism and determine the usefulness of FS lignan-mediated radioprotection. SDG is currently being evaluated in clinical trials worldwide a fact that will facilitate ultimately testing the findings of this proposal in the clinic on lung cancer radiotherapy patients. PUBLIC HEALTH RELEVANCE: The usefulness of thoracic radiotherapy is limited by lung sensitivity to irradiation doses necessary to eradicate malignant cells. Therefore, the development of radioprotectors that would increase the therapeutic ratio of radiotherapy is urgently needed. Reactive oxygen species induced by ionizing radiation contribute significantly to the pathogenesis of fibrotic lung disease. We hypothesize that dietary FS lignans mediate the activation of antioxidant and cytoprotective genes as a novel therapeutic strategy to alleviate radiation pneumonopathy. In Aim 1 we'll explore the potential pulmonary radioprotective efficacy of FS lignans in a well-established murine model of radiation lung injury using dietary formulations Secoisolariciresinol Diglucoside (SDG), the main FS lignan precursor. In Aim 2 we will determine if Nrf2/ARE activation is implicated in the mechanism of their protection and establish cell specificity of their action. In Aim 3 we will evaluate lignan-mediated radiosensitization of lung cancer cells using a novel K-ras mouse model of orthotopic lung cancer. Successful completion of the proposed studies will elucidate the mechanism and determine the usefulness of FS lignan-mediated radioprotection enabling future clinical trials in the context of lung cancer radiotherapy.

描述（由申请人提供）：胸腔放射疗法的有用性极大地受到对消除恶性细胞所需的辐射剂量的肺部敏感性的限制。多达30％因肺癌辐照的患者和其他约10-15％的其他胸部肿瘤学患者发生了临床上显着的辐射毒性。保护“正常”肺实质免受辐射损伤的需求损害了肿瘤放射疗法剂量的递送。因此，迫切需要增加放射疗法治疗比率的放射保护剂。电离辐射引起的活性氧物种对纤维化肺部疾病的发病机理显着贡献。然而，从氧化组织侮辱到晚期纤维化的分子途径尚不清楚，目前，没有自由基清除剂提供可接受的肺辐射保护水平，而没有严重的副作用。我们和其他人已经表明，抗氧化剂疗法减轻了辐射诱导的纤维化肺疾病，我们的初步数据表明，全graxsseed（FS）或FS Lignans，具有已知抗氧化剂，抗炎性，抗炎性和抗癌特性的生物活性化合物，诱导抗氧化型抗氧化剂，以启动性抗元素的抗性激活。此外，当在我们的胸椎辐射诱导的肺炎的小鼠模型中评估时，全谷物FS饮食可强大增加小鼠的存活，废除肺纤维化并减少氧化组织损伤，同时放射增强肺肿瘤。因此，我们假设饮食FS木质脂肪介导的抗氧化基因激活可能是减轻肺炎辐射肺炎的一种新型治疗策略。在当前的研究中，在AIM 1中，我们将使用Secoisoilariciresinol digucoside（SDG）的饮食中FS Lignan前体的饮食制剂探索FS Lignans的潜在肺辐射疗法的潜在肺部辐射肺损伤模型。在AIM 2中，我们将确定是否激活是否与保护机理有关，并确定其作用的细胞特异性。在AIM 3中，我们将使用新型的原位肺癌的K-RAS小鼠模型评估木质蛋白介导的肺癌细胞的放射敏化。成功完成拟议的研究将阐明该机制并确定FS木质介导的放射保护的有用性。目前，在全球临床试验中对可持续发展目标进行了评估，这一事实将有助于最终在肺癌放射疗法患者的诊所中测试该提案的发现。公共卫生相关性：胸腔放射疗法的有用性受到根除恶性细胞所需的辐射剂量的肺敏感性的限制。因此，迫切需要急需增加放射治疗比率的放射保护剂的发展。电离辐射引起的活性氧物种对纤维化肺部疾病的发病机理显着贡献。我们假设饮食中的FS木质剂介导抗氧化剂和细胞保护基因的激活，作为一种减轻辐射性肺炎的新型治疗策略。在AIM 1中，我们将使用饮食配方secoisoilariciresinol digucoside（SDG）（Main FS lignan propursor）探索FS木质杆FS木质杆的潜在肺部放射保护功效。在AIM 2中，我们将确定NRF2/是激活是否与保护机制有关，并确定其作用的细胞特异性。在AIM 3中，我们将使用新型的原位肺癌的K-RAS小鼠模型评估木质蛋白介导的肺癌细胞的放射敏化。成功完成拟议的研究将阐明该机制，并确定FS木质介导的放射保护的有用性，从而在肺癌放射疗法的背景下实现未来的临床试验。