Quantifying NNK metabolites to facilitate Kava lung cancer prevention clinical translation

量化 NNK 代谢物以促进 Kava 肺癌预防临床转化

基本信息

批准号：
10512091
负责人：
CHENGGUO XING
金额：
$ 7.63万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10512091
关键词：
3-methyladenine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone A/J Mouse Address Animal Model Animals Beverages Biological Markers Cancer Etiology Carcinogens Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Clinical Treatment Colon Consumption DNA Damage Data Development Diagnosis Disease Double-Blind Method Drug Metabolic Detoxication Early Diagnosis Enzymes Epidemiology Female Glucuronides Glycols Goals Hand Human Incidence Individual Institutional Review Boards Intervention Kava Light Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Methods Monitor Pacific Islander Pacific Islands Participant Pathway interactions Placebo Control Plasma Plasma Proteins Population Prevention strategy Preventive Process Prostate Randomized Recording of previous events Relative Risks Risk Risk Reduction Sampling Single Nucleotide Polymorphism Sleep Smoker Stress Time Tobacco Tobacco Use Cessation Tobacco use Translations Urine adduct animal data base cancer chemoprevention cancer risk carcinogenesis carcinogenicity cigarette smoking clinical translation epidemiologic data high risk improved in vivo individualized prevention insight lung basal segment lung cancer prevention lung carcinogenesis male personalized intervention pilot trial pre-clinical prevent success tobacco specific lung carcinogen tumorigenesis urinary

项目摘要

ABSTRACT Lung cancer causes the most deaths among all cancers. Given the limited success in its early diagnosis and clinical treatment, risk reduction is essential in order to improve lung cancer management. Tobacco cessation should be the primary approach among smokers for lung cancer risk reduction. Current cessation interventions, however, are not very effective. Preventing tobacco-induced carcinogenesis could be complementary. Supported by human epidemiological data, pre-clinical animal data, a pilot trial, and equipped with mechanistic insights, kava is a promising candidate to reduce lung cancer risk among addicted smokers. Kava, which originates from the South Pacific Islands as a beverage, reduces stress and improves sleep. An inverse relationship between kava consumption and cancer incidence, particularly lung cancer, among the South Pacific Islanders suggests its potential in reducing cancer risks. We demonstrated that kava completely blocked lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (a tobacco specific lung carcinogen, commonly known as NNK) and other cancers in lab animals. One underlying mechanism is to enhance carcinogen detoxification and thus reduce carcinogen-induced DNA damage. Consistent with lab animal data, our pilot trial results showed that kava reduced lung cancer risk biomarkers among smokers. In order to improve kava’s translational feasibility and to maximize its lung cancer preventive benefits, this self-contained study aims to evaluate the potential of five mechanism-based non-invasive quantitative biomarkers in timely monitoring the efficacy of kava intervention and more importantly to explore the opportunities of kava precision prevention among smokers by analyzing these biomarkers and potential SNPs using banked pre-, during-, and post-kava urine, plasma and buffy coat samples from 21 smoker participants. Aim 1. To quantify three NNK-based urinary metabolites – free NNAL, NNAL-N-gluc and NNAL-O-gluc in the urine samples among 21 participants collected from the pilot trial before kava exposure (Day 0), during kava exposure (Day 4), and after kava exposure (Day 7). Specific UGT SNPs will be analyzed as well. Aim 2. To quantify two NNK-based plasma protein adducts – HPB and Diol in the plasma samples among 21 participants collected from the pilot trial before kava exposure (Day 0), during kava exposure (Day 4), and after kava exposure (Day 7).

抽象的鉴于其早期诊断和治疗的成功有限，肺癌是所有癌症中死亡人数最多的。临床治疗中，降低风险对于改善肺癌管理至关重要。应成为吸烟者降低肺癌风险的主要方法，然而，预防烟草诱发的致癌作用并不是很有效。以人类流行病学数据、临床前动物数据、试点试验为支持，并配备机制据了解，卡瓦是降低吸烟成瘾者患肺癌风险的有前途的候选者。源自南太平洋岛屿，作为一种饮料，可以减轻压力并改善睡眠。南太平洋地区卡瓦消费量与癌症发病率（特别是肺癌）之间的关系岛民认为卡瓦具有降低癌症风险的潜力。我们证明卡瓦可以完全阻断肺部。 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮（一种烟草特异性肺癌致癌物，通常称为 NNK）和实验室动物的其他癌症的一种潜在机制是增强。致癌物解毒，从而减少致癌物引起的 DNA 损伤，与实验室动物数据一致，我们的试点试验结果表明，卡瓦酒可以降低吸烟者患肺癌的风险生物标志物。这项独立的研究旨在研究卡瓦的转化可行性并最大限度地发挥其肺癌预防作用评估五种基于机制的非侵入性定量生物标志物在及时监测疾病方面的潜力卡瓦干预的有效性，更重要的是探索卡瓦精准预防的机会通过使用储存的卡瓦前、中和后分析这些生物标志物和潜在的 SNP，对吸烟者进行调查来自 21 名吸烟者参与者的尿液、血浆和血沉棕黄层样本目标 1. 量化三种基于 NNK 的尿液。代谢物 – 收集的 21 名参与者的尿液样本中含有游离 NNAL、NNAL-N-gluc 和 NNAL-O-gluc 来自卡瓦暴露前（第 0 天）、卡瓦暴露期间（第 4 天）和卡瓦暴露后（第 0 天）的试点试验 7). 还将分析特定的 UGT SNP。目标 2. 定量两种基于 NNK 的血浆蛋白加合物 – 21 名参与者在接触卡瓦之前从试点试验中收集的血浆样本中含有 HPB 和二醇（第 0 天）、接触卡瓦期间（第 4 天）和接触卡瓦之后（第 7 天）。