Secoisolariciresinol Diglucoside (SDB) Protection in Radiation Pheumonopathy

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，从氧化组织损伤到晚期辐射纤维化的分子途径尚不清楚，目前，没有自由基清除剂可以提供可接受水平的肺放射保护而不会产生严重的副作用。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的小鼠模型中进行评估时，全谷物FS饮食有力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。

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.