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 在所有癌症中，肺癌导致的死亡人数最多。鉴于早期诊断和治疗的成功有限 临床治疗中，降低风险是提高肺癌管理水平的关键。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，效果并不是很好。预防烟草致癌可能是相辅相成的。 在人类流行病学数据、临床前动物数据的支持下，进行试点试验，并配备机械式 洞察，卡瓦是一个有希望的候选人，以降低吸烟成瘾者患肺癌的风险。卡瓦，它 源自南太平洋群岛，是一种饮料，可以缓解压力和改善睡眠。一个倒数 南太平洋地区卡瓦消费与癌症发病率，特别是肺癌发病率的关系 岛民表示，它在降低癌症风险方面具有潜力。我们证明了卡瓦完全阻断了肺 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(一种烟草特有的肺癌致癌物， 通常被称为NNK)和其他实验动物癌症。一个潜在的机制是增强 使致癌物解毒，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，卡瓦降低了吸烟者患肺癌的风险生物标记物。为了提高 Kava的翻译可行性和最大限度地提高其肺癌预防效益，这项独立的研究旨在 评价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准预防的机会 通过分析这些生物标志物和潜在的SNP，使用银行的卡瓦前、卡瓦期间和卡瓦后 21名吸烟者的尿液、血浆和黄褐色外套样本。目的1.定量检测三种NNK基尿液 21名受试者尿样中无代谢产物NNAL、NNAL-N-Gluc和NNAL-O-Gluc 在卡瓦曝光之前(第0天)、在卡瓦曝光期间(第4天)和在卡瓦曝光之后(第4天)进行的飞行员试验 7)。还将分析特定的UGT SNPs。目的2.定量两种基于NNK的血浆蛋白加合物- 卡瓦暴露前21名受试者血浆样本中HPB和Diol的含量 (第0天)、在卡瓦暴露期间(第4天)和在卡瓦暴露之后(第7天)。