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

• 批准号: 8307407
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307407
• 关键词: A549; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Biological Assay; Cell Death; Cells; Cereals; Chemopreventive Agent; Chest; Clinic; Clinical Trials; Complex; Data; Development; Diet; Dietary Fiber; Dietary Formulations; Dietary Supplementation; Dose; Endothelial Cells; Ensure; Enzyme Gene; Enzymes; Epidermal Growth Factor Receptor; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Fibrosis; Flax; Free Radical Scavengers; Future; Generations; Genes; Goals; Growth; Human; In Vitro; Inflammation; Intestines; Ionizing radiation; K-ras mouse model; Knockout Mice; Lignans; Lung; Lung Neoplasms; Lung diseases; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Omega-3 Fatty Acids; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pneumonia; Property; Proto-Oncogene Proteins c-akt; Radiation; Radiation Injuries; Radiation Pneumonitis; Radiation Tolerance; Radiation Toxicity; Radiation therapy; Radioprotection; Radiosensitization; Reactive Oxygen Species; Reporter; Response Elements; Role; Signal Pathway; Specificity; Staging; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Effect; Thoracic Oncology; Time; Tissues; Toxic effect; Transcriptional Activation; Transgenic Organisms; angiogenesis; base; cancer cell; cancer radiation therapy; clinically significant; cytotoxic; design; enzyme therapy; flaxseed lignan; improved; in vivo; irradiation; killings; lung injury; mouse model; neoplastic cell; novel; novel therapeutics; protective effect; secoisolariciresinol diglucoside; transcription factor; tumor; tumor growth

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.

描述（由申请人提供）： 肺部对根除恶性细胞所需的辐射剂量的敏感性极大地限制了胸部放射治疗的有效性。高达 30% 的肺癌患者和约 10-15% 的其他胸部肿瘤患者会出现具有临床意义的放射毒性。保护“正常”肺实质免受辐射损伤的需要会影响杀肿瘤放射治疗剂量的传递。因此，迫切需要能够提高放射治疗效率的放射防护剂。电离辐射诱导的活性氧对纤维化肺病的发病机制有重要影响。然而，从氧化组织损伤到晚期放射性纤维化的分子途径尚不清楚，目前还没有自由基清除剂能够提供可接受水平的肺部放射防护且没有严重副作用。我们和其他人已经证明，抗氧化酶疗法可以减轻辐射引起的纤维化肺病，并且我们的初步数据表明，全麦亚麻籽（FS）或FS木脂素（具有已知抗氧化、抗炎和抗癌特性的生物活性化合物）可诱导小鼠肺部抗氧化酶基因的转录激活。此外，当在我们的胸部放射引起的肺炎小鼠模型中进行评估时，全谷物FS饮食显着提高了小鼠的存活率，消除了肺纤维化并减少了氧化组织损伤，同时使肺肿瘤放射增敏。因此，我们假设膳食 FS 木脂素介导的抗氧化基因激活可能是减轻放射性肺炎的一种新的治疗策略。在当前的研究中，目标 1 我们将使用主要 FS 木脂素前体 Secoisolariciresinol Diglucoside (SDG) 的饮食配方，在成熟的放射性肺损伤小鼠模型中探索 FS 木脂素的潜在肺辐射防护功效。在目标 2 中，我们将确定 ARE 激活是否与保护机制有关，并确定其作用的细胞特异性。在目标 3 中，我们将使用新型 K-ras 小鼠原位肺癌模型评估木酚素介导的肺癌细胞放射增敏作用。成功完成拟议的研究将阐明 FS 木脂素介导的辐射防护的机制并确定其有效性。 SDG 目前正在全球范围内的临床试验中进行评估，这将有助于最终在肺癌放射治疗患者的临床试验中测试该提案的结果。