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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：
10683294
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/10683294
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 Female Glycols Goals Human Incidence Individual Institutional Review Boards Intervention Kava Light Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Methods Monitor Observational epidemiology 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 Smoker Tobacco Tobacco Use Cessation Tobacco use Translations Urine adduct animal data cancer chemoprevention cancer risk carcinogenesis carcinogenicity cigarette smoking clinical translation epidemiologic data high risk population improved improvement on sleep in vivo individualized prevention insight lung basal segment lung cancer prevention lung carcinogenesis male personalized intervention pilot trial pre-clinical prevent preventive intervention stress reduction 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).

摘要