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: 7693716
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 31.97万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693716
• 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; Cessation of life; 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

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)： 胸部放射治疗的有效性受到肺部对根除恶性细胞所需的照射剂量的敏感性的极大限制。临床上，高达30%的肺癌患者和大约10%-15%的其他胸部肿瘤患者发生了显著的辐射毒性。保护“正常”肺实质免受辐射损伤的需要影响了杀瘤放射剂量的提供。因此，迫切需要能够提高放射治疗比率的放射防护剂。电离辐射诱导的活性氧在纤维化肺病的发病机制中起重要作用。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在没有严重副作用的情况下提供可接受的肺辐射防护水平。我们和其他人已经证明抗氧化酶疗法可以缓解辐射诱导的纤维化肺部疾病，我们的初步数据表明，全谷物亚麻籽(FS)或FS木脂素是一种具有已知抗氧化、抗炎和抗癌特性的生物活性化合物，可诱导小鼠肺中抗氧化酶基因的转录激活。此外，在我们的胸部放射诱导的肺病小鼠模型中进行评估时，全谷物FS饮食显著增加了小鼠的存活率，消除了肺纤维化，减少了氧化组织损伤，同时使肺癌放射增敏。因此，我们推测膳食FS木脂素介导的抗氧化基因激活可能是缓解放射性肺炎的一种新的治疗策略。在目前的研究中，在目标1中，我们将使用FS木脂素的主要前体Secosolariciiciresinol DigLucoside(SDG)的饮食配方，在已建立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效果。在目标2中，我们将确定ARE激活是否与保护机制有关，并建立其作用的细胞特异性。在目标3中，我们将使用一种新的K-ras小鼠原位肺癌模型来评估木脂素介导的肺癌细胞的放射增敏作用。拟议研究的成功完成将阐明这一机制并确定FS木脂素介导的放射防护的有用性。SDG目前正在世界各地的临床试验中进行评估，这一事实将有助于在肺癌放射治疗患者的临床上最终测试这一建议的结果。 公共卫生相关性： 胸部放射治疗的有效性受到肺部对根除恶性细胞所需的照射剂量的敏感性的限制。因此，迫切需要开发能够提高放射治疗比率的放射防护剂。电离辐射诱导的活性氧在纤维化肺病的发病机制中起重要作用。我们假设膳食FS木脂素介导抗氧化剂和细胞保护基因的激活，作为减轻放射性肺炎的一种新的治疗策略。在目标1中，我们将使用FS木脂素的主要前体Secosolariciiciresinol DigLucoside(SDG)的饮食配方，在已建立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效果。在目标2中，我们将确定Nrf2/ARE的激活是否与它们的保护机制有关，并建立它们作用的细胞特异性。在目标3中，我们将使用一种新的K-ras小鼠原位肺癌模型来评估木脂素介导的肺癌细胞的放射增敏作用。拟议研究的成功完成将阐明这一机制，并确定FS木脂素介导的放射防护的有用性，从而使未来的肺癌放射治疗临床试验成为可能。