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）：充足的临床前数据表明葡萄籽提取物（GSE）具有抗癌特性。葡萄籽含有高含量的多酚，包括原花青素。这些植物化学物质已被证明可以调节致癌机制，包括抑制环氧合酶-2 (COX-2) 和前列腺素 E2 (PGE2) 途径，并抑制肺癌动物模型中的肿瘤生长。虽然食用 GSE 被认为可以促进身体健康并预防癌症，但缺乏实际的临床证据。因此，我们假设口服 GSE 是安全的，可以有利地调节与肺部肿瘤发生相关的机制，并且可能有助于肺癌的化学预防。为了检验这些假设，将在 20 名重度吸烟者或戒烟者（吸烟年数 > 30 包）中进行为期 3 个月的单组、剂量递增 I 期肺癌化学预防研究，使用口服 GSE。目标#1：将确定 3 个月 GSE 的安全性、耐受性和 PK/PD，以及支气管镜标本用于监测肺部 GSE 生物活性的效用。受试者将接受一系列荧光支气管镜检查，包括支气管肺泡灌洗（BAL）、支气管刷检、支气管活检，以及治疗前后血液和尿液样本的收集。将通过测量处理前后样品中的葡萄籽原花青素 (GSP) 和代谢物来进行修改后的 PK 研究。此外，治疗前和治疗后血浆和 BAL 将用于与非小细胞肺癌细胞 (NSCLC) 系 A549 和支气管癌前细胞系 1198 共培养。口服 GSE 在肺中的生物活性将通过以下方法进行评估：比较 BAL 共培养与血浆共培养。 GSE 的抗肿瘤机制将通过比较其治疗前后的生物活性来评估，通过以下调节来测量：1) 与血浆和 BAL 共培养的 A549 和 1198 细胞中的增殖指数、COX-2 表达和 PGE2 产生; 2）支气管Ki-67标记指数； 3）支气管组织病理学； 4) 15(S)-羟基二十碳四烯酸(15-HETE)、白细胞介素(IL)-6、IL-10、IL-12和C反应蛋白(CRP)； 5) 癌症相关、通路特异性基因表达谱（GEP）； 6) 通过 BAL 细胞、支气管刷检和活检中的 micro(mi) RNA 表达评估表观遗传特征。目标#2：将描述 mir-19a、mir-19b 和 mir-106b 在介导 GSE 抗肿瘤作用中的作用，并检查血浆 mir-19a、-19b、-106b 作为替代终点生物标志物的潜力（ SEBM）用于治疗监测。在初步研究中，我们已确定 mir-19a、mir-19b 和 -106b 是 A549 和 H1299 细胞中 GSE 下调最显着的 miRNA。这些 miRNA 是众所周知的肺癌癌基因，并且是最近一份报告中确定为肺癌发展预测因子的主要血浆 miRNA 之一。因此，我们将测量治疗前和治疗后血浆中的这些 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 对抗肺癌的可行性和机制效应提供重要见解，有助于识别 SEBM 并为未来的临床试验奠定基础。