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: 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
• 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

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对消除恶性细胞所必需的照射剂量的敏感性的极大限制。在高达30%的肺癌放疗患者和约10-15%的其他胸部肿瘤患者中发生临床显著的辐射毒性。保护“正常”肺实质免受辐射损伤的需要损害了杀肿瘤放射治疗剂量的递送。因此，迫切需要能提高放射治疗率的放射防护剂。电离辐射诱导的活性氧在纤维化肺疾病的发病机制中起重要作用。然而，从氧化性组织损伤到晚期放射性纤维化的分子途径尚不清楚，此时，没有自由基清除剂提供可接受的肺放射保护水平而没有严重的副作用。我们和其他人已经表明，抗氧化酶治疗可减轻辐射诱导的纤维化肺病，我们的初步数据表明，全谷亚麻籽（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）诱导小鼠肺中抗氧化酶基因的转录激活。此外，当在我们的胸部辐射诱导的肺病小鼠模型中进行评估时，全谷物FS饮食稳健地增加了小鼠存活率，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，我们推测膳食FS木脂素介导的抗氧化基因的激活可能是一种新的治疗策略，以减轻放射性肺炎。在当前的研究中，在目的1中，我们将探索FS木脂素在使用主要FS木脂素前体开环异落叶松树脂酚二葡糖苷（SDG）的饮食制剂的良好建立的放射性肺损伤的鼠模型中的潜在肺放射保护功效。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，我们将使用新的原位肺癌K-ras小鼠模型评估木脂素介导的肺癌细胞的放射增敏作用。成功完成拟议的研究将阐明机制，并确定FS木脂素介导的辐射防护的有用性。SDG目前正在全球临床试验中进行评估，这将有助于最终在肺癌放疗患者的临床中测试该提案的结果。 公共卫生相关性： 胸部放射治疗的有效性受到肺对消除恶性细胞所需的照射剂量的敏感性的限制。因此，迫切需要开发出能提高放射治疗率的放射防护剂。电离辐射诱导的活性氧在纤维化肺疾病的发病机制中起重要作用。我们推测，膳食FS木脂素介导的抗氧化和细胞保护基因的激活作为一种新的治疗策略，以减轻放射性肺炎。在目的1中，我们将探索FS木脂素在使用膳食制剂Secoisolaricirestinol Diglucoside（SDG）（主要FS木脂素前体）的良好建立的放射性肺损伤小鼠模型中的潜在肺放射保护功效。在目标2中，我们将确定Nrf 2/ARE激活是否与其保护机制有关，并建立其作用的细胞特异性。在目标3中，我们将使用新的原位肺癌K-ras小鼠模型评估木脂素介导的肺癌细胞的放射增敏作用。成功完成拟议的研究将阐明机制，并确定FS木脂素介导的辐射防护的有用性，使未来的临床试验中的肺癌放疗的背景下。