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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：
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
项目类别：
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

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.

描述（由申请人提供）：