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: 8583907
• 负责人: JENNY T MAO
• 金额: $ 17.49万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583907
• 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; public health relevance; 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）：丰富的临床前数据表明，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（考克斯-2）和前列腺素E2（PGE 2）途径，并抑制肺癌动物模型中的肿瘤生长。虽然GSE的消费被认为可以促进健康和预防癌症，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肿瘤发生相关的机制，并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（> 30包年吸烟）中进行为期3个月的口服GSE单组、剂量递增I期肺癌化学预防研究。目标一：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中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、支气管活检以及沿着采集治疗前和治疗后的血液和尿液样本。将通过测量治疗前和治疗后样本中的葡萄籽原花青素（GSP）和代谢产物进行改良的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的共培养。将通过比较BAL共培养物与血浆共培养物来评估口服GSE在肺中的生物活性。GSE的抗肿瘤机制将通过比较其治疗前和治疗后的生物活性来评估，所述生物活性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、考克斯-2表达和PGE 2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）;和6）通过BAL细胞、支气管刷检和活组织检查中的微（mi）RNA表达评估的表观遗传谱。目标二：将表征mir-19 a、mir-19 b和mir-106 b在介导GSE的抗肿瘤作用中的作用，并检查血浆mir-19 a、mir-19 b和mir-106 b作为治疗监测的替代终点生物标志物（SEBM）的潜力。在初步研究中，我们已经确定了mir-19 a，mir-19 b和-106b作为A549和H1299细胞中GSE最显著下调的miRNAs。这些miRNAs是肺癌中众所周知的癌细胞，并且是在最近的报告中鉴定为肺癌发展的预测因子的主要血浆miRNAs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SEBM用于GSE治疗的效用。该研究的结果将为GSE对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。