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

• 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
• 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

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).

摘要 肺癌是所有癌症中死亡人数最多的。鉴于其早期诊断的成功率有限， 为了改善肺癌的管理，降低风险是至关重要的。戒烟 应该是吸烟者降低肺癌风险的主要方法。目前的戒烟干预措施， 然而，它们不是非常有效。防止烟草引起的致癌作用可以起到补充作用。 在人类流行病学数据、临床前动物数据、中试试验的支持下， 根据专家的见解，卡瓦是一种很有前途的候选药物，可以降低吸烟成瘾者患肺癌的风险。卡瓦， 原产于南太平洋群岛，是一种饮料，可以减轻压力，改善睡眠。逆 在南太平洋，卡瓦消费与癌症发病率，特别是肺癌发病率之间的关系 岛民们认为它在降低癌症风险方面具有潜力。我们证明卡瓦完全阻断了肺 由4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（烟草特异性肺致癌物， 通常称为NNK）和实验室动物中的其他癌症。一个潜在的机制是增强 致癌物解毒，从而减少致癌物引起的DNA损伤。与实验动物数据一致， 我们的初步试验结果表明，卡瓦降低了吸烟者患肺癌的风险生物标志物。为了提高 卡瓦的翻译可行性，并最大限度地提高其预防肺癌的好处，这个独立的研究目的是 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 卡瓦干预的有效性，更重要的是探索卡瓦精确预防的机会 通过分析这些生物标志物和潜在的SNP，使用库中的卡瓦前，卡瓦期间和卡瓦后， 来自21名吸烟者参与者的尿液、血浆和血沉棕黄层样品。目标1.为了定量三种基于NNK的尿 代谢物-在采集的21名参与者的尿液样本中游离NNAL、NNAL-N-gluc和NNAL-O-gluc 在卡瓦暴露前（第0天）、卡瓦暴露期间（第4天）和卡瓦暴露后（第4天）， 7）。还将分析特定的UGT SNP。目标2.为了定量两种基于NNK的血浆蛋白加合物- 在卡瓦暴露前从先导试验中收集的21名参与者的血浆样本中的HPB和Diol (Day 0）、卡瓦暴露期间（第4天）和卡瓦暴露后（第7天）。