Feasibility of grape seed extract for lung cancer chemoprevention

葡萄籽提取物用于肺癌化学预防的可行性

• 批准号: 8926891
• 负责人: JENNY T MAO
• 金额: $ 11.13万
• 依托单位: BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926891
• 关键词: A549; Adverse effects; Adverse reactions; Aftercare; Animal Model; Biological Availability; Biological Markers; Biological Models; Biological Monitoring; Biopsy; Blood; Blood Tests; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Bronchoscopy with Bronchoalveolar Lavage; C-reactive protein; Cancer Etiology; Cancer cell line; Cause of Death; Cell Extracts; Cell Line; Cells; Cessation of life; Chemopreventive Agent; Clinical; Clinical Trials; Coculture Techniques; Collection; Colorectal Cancer; Common Terminology Criteria for Adverse Events; Consumption; Country; Coxibs; Cytochrome P450 3A4; Data; Development; Dinoprostone; Disease; Dose; Drug Kinetics; Eicosatetraenoic Acids; Epigenetic Process; Fluorescence Bronchoscopy; Food Supplements; Future; Gene Expression; Genetic Transcription; H1299; Health; Health Food; Histopathology; Human; In Vitro; Inflammatory; Interleukin-10; Interleukin-12; Interleukin-6; Label; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mediating; MicroRNAs; Molecular Profiling; Monitor; Non-Small-Cell Lung Carcinoma; Oral; Oral Administration; Pathway interactions; Pharmacodynamics; Phase; Phase I Clinical Trials; Physiological; Phytochemical; Plasma; Premalignant Cell; Preparation; Proanthocyanidins; Production; Proliferation Marker; Property; Questionnaires; Reporting; Role; S-Phase Fraction; Safety; Sampling; Signal Pathway; Smoker; Smoking; Specimen; Staging; Surrogate Endpoint; Testing; Therapeutic; Urine; Visit; arm; base; cancer chemoprevention; cancer therapy; cyclooxygenase 2; effective therapy; grape seed; grape seed extract; high risk; high throughput technology; in vivo; indexing; inflammatory marker; insight; lung cancer prevention; lung tumorigenesis; malignant breast neoplasm; neoplastic; polyphenol; pre-clinical; prevent; tumor growth

DESCRIPTION (provided by applicant): Ample preclinical data suggests that grape seed extract (GSE) possesses anticarcinogenic properties. Grape seed contains high levels of polyphenols, including proanthocyanidins. These phytochemicals have been shown to modulate carcinogenic mechanisms, including inhibition of the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways, and inhibit tumor growth in animal models of lung cancer. While consumption of GSE is believed to promote good health and prevent cancer, actual clinical evidence is lacking. We therefore hypothesize that oral administration of GSE is safe, can favorably modulate mechanisms associated with lung tumorigenesis, and may be useful for lung cancer chemoprevention. To test these hypotheses, a single arm, dose escalation phase I lung cancer chemoprevention study of 3 months with an oral GSE will be conducted in 20 heavy active or ex-smokers (> 30 pack years of smoking). Aim #1: will determine the safety, tolerability and PK/PD of 3 months of GSE and the utility of bronchoscopic specimens for monitoring the bioactivity of GSE in the lung. Subjects will undergo serial fluorescence bronchoscopies with bronchoalveolar lavage (BAL), bronchial brushings, bronchial biopsies, along with collections of pre- and post-treatment blood and urine samples. A modified PK study will be performed by measuring grape seed proanthocyanidins (GSP) and metabolites in pre- and post-treatment samples. In addition, Pre- and post treatment plasma and BAL will be used in co-cultures with the nonsmall cell lung cancer cell (NSCLC) line A549 and the bronchial premalignant cell line 1198. The bioactivity of oral GSE in the lung will be assessed by comparing BAL co-culture with plasma co-cultures. The anti-neoplastic mechanisms of GSE will be assessed by comparing its bioactivity pre- and post-treatment as measured by modulations of: 1) proliferation index, COX-2 expression and PGE2 production in A549 and 1198 cells co-cultured with plasma and BAL; 2) Bronchial Ki-67 labeling index; 3) bronchial histopathology; 4) 15(S)-hydroxy-eicosatetraenoic acid (15-HETE), interleukin (IL)-6, IL-10, IL-12 and C-reactive protein (CRP); 5) cancer relevant, pathway specific gene expression profiles (GEP); and 6) epigenetic profiles assessed by micro(mi) RNA expression in BAL cells, bronchial brushing and biopsies. Aim #2: will characterize the roles of mir-19a, mir-19b, and mir-106b in mediating the anti-neoplastic effects of GSE and examine the potential of plasma mir-19a, -19b, -106b as surrogate endpoint biomarkers (SEBM) for therapeutic monitoring. In preliminary studies, we have identified mir-19a, mir-19b, and -106b as the most significantly down-regulated miRNAs by GSE in A549 and H1299 cells. These miRNAs are well known oncomirs in lung cancer and are among the major plasma miRNAs identified to be predictors of lung cancer development in a recent report. Therefore, we will measure these miRNA levels in plasma pre- and post-treatment to determine their utility as SEBM for GSE treatment. Findings from the study will provide important insights into the feasibility and mechanistic effects of GSE against lung cancer, help identify SEBM and set the stage for future clinical trials.

描述（由申请人提供）：足够的临床前数据表明葡萄种子提取物（GSE）具有抗癌特性。葡萄种子含有高水平的多酚，包括原腺苷素。这些植物化学物质已被证明可以调节致癌机制，包括抑制环氧酶-2（COX-2）和前列腺素E2（PGE2）途径，以及抑制肺癌动物模型的肿瘤生长。虽然据信GSE的消费可以促进健康并预防癌症，但缺乏实际的临床证据。因此，我们假设口服GSE是安全的，可以很好地调节与肺部肿瘤发生相关的机制，并且可能对肺癌化学预防有用。为了检验这些假设，将在20个激烈的或前吸烟者（> 30年的吸烟年）中进行一个单臂，I期I肺癌化学预防研究3个月的肺癌化学预防研究。 AIM＃1：将确定3个月GSE的安全性，耐受性和PK/PD，以及支气管镜标本的效用，以监测肺中GSE的生物活性。受试者将与支气管肺泡灌洗（BAL），支气管刷，支气管活检以及治疗前和治疗后血液和尿液样品的集合一起进行连续荧光支气管镜。修改后的PK研究将通过测量葡萄种子原腺苷（GSP）和治疗后样品中的代谢产物进行。此外，治疗前和治疗后血浆和BAL将用于与Nonsmall细胞肺癌细胞（NSCLC）系A549和支气管前态度细胞细胞系1198的共培养。肺中口服GSE的生物活性将通过将BAL COURTURE与血浆培养物进行比较来评估。 GSE的抗塑性机制将通过比较以下调制测量的A549和1198细胞的增殖指数，COX-2表达和PGE2产生，以比较其生物活性前和治疗后的生物活性机制，并进行了比较。 2）支气管KI-67标签指数； 3）支气管组织病理学； 4）15（s） - 羟基 - 耐氧化甲酸（15-赫特），白介素（IL）-6，IL-10，IL-10，IL-12和C反应蛋白（CRP）; 5）癌症相关，途径特异性基因表达谱（GEP）； 6）通过微细胞，支气管刷和活检评估的表观遗传谱。 AIM＃2：将表征miR-19a，miR-19b和miR-106b在介导GSE的抗塑性作用中的作用，并检查血浆miR-19a，-19b，-106b作为替代端点生物标志物（SEBM）的潜力。在初步研究中，我们已经将miR-19a，miR-19b和-106b确定为GSE在A549和H1299细胞中最显着下调的miRNA。这些miRNA在肺癌中众所周知，是在最近的一份报告中被确定为肺癌发育预测指标的主要等离子体miRNA之一。因此，我们将在治疗前后血浆中测量这些miRNA水平，以确定它们作为GSE治疗的SEBM的效用。该研究的结果将为GSE对肺癌的可行性和机械影响提供重要见解，有助于识别SEBM并为将来的临床试验奠定了基础。