DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

A Chemoprevention Trial to Study the Effects of High Tea Consumption on Smoking-Related Oxidative Stress

Principal Investigator: HAKIM, IMAN
Institution Receiving Award: ARIZONA, UNIVERSITY OF, TUCSON
Program: PRMRP
Proposal Number: PR023104
Award Number: DAMD17-03-1-0053
Funding Mechanism: Investigator Initiated Research Award
Partnering Awards:
Award Amount: $1,261,963.00


TECHNICAL ABSTRACT

Background: Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure and lack of protective factors. Because of the link between internal alpha radiation exposure and lung cancer, there were 20% more lung cancer deaths than expected among workers involved in the production of nuclear materials for the U.S. government's nuclear weapons program. Histologic evaluation of the airway abnormality among Gulf War veterans showed chronic inflammation of the upper airways and inspiratory airflow limitation in a number of Gulf War veterans. Moreover, the work of US Marines in a moderate-altitude cold-weather environment is accompanied by increased oxidative stress. A cancer prevention strategy targeting this largely at-risk population is necessary.

Objective/Hypothesis: The primary hypothesis is that regular tea consumption, of either black or green tea, by subjects with chronic obstructive lung disease (COPD) and 25 or more pack-years of smoking history will induce (1) an increase in plasma catechins and (2) a decrease in the DNA and lipid oxidative stress status as measured by 8-hydroxy-deoxyguanosine (8-OHdG), 8-F2 Isoprostanes (8-epi-PGF2), Malondealdehyde (MDA), ethanes, and Nitric Oxide (NO).

Specific Aims: The main aims of the proposal are (1) to determine each subject's baseline history of smoking, diet and tea intake, plasma catechins, and levels of 8-OhDG, 8-epi-PGF2, ethanes, NO, and MDA at baseline; (2) to randomize at least 180 eligible COPD chronic and former smokers into one of three interventions: black tea extract, green tea extract, or matching placebo (clinical phase IIb trial) to study the effect of tea consumption on DNA (8-OhDG) and lipid (8-epi-PGF2, MDA, ethanes) damage in blood, urine, and exhaled breath condensate (EBC); and (3) to determine the changes of 8-OhDG, 8-epi-PGF2, ethanes, NO, and MDA between the three intervention groups after 6 months of the intervention.

Study Design: We propose to conduct a 6-month randomized, placebo-controlled, double-blinded chemopreventive trial in a group of COPD subjects with 25 or more pack-years of smoking history. The participants will be stratified on smoking status (current or former) and gender and will be randomized to green or black tea extracts or a control intervention (matching placebo). Levels of 8-OHdG will be used to measure DNA damage and levels of 8-epi-PGF2, MDA, and ethanes will be used to measure lipid damage. Changes in biomarkers of oxidative damage will be measured in urine, blood, and exhaled breath condensate.

Relevance: Changes in dietary habits with the intake of more cancer-chemopreventive agents appear to be a practical approach for cancer prevention in subjects with increased oxidative stress as is the case of subjects with COPD and >/= 25 pack-years of smoking history. The present study will investigate the ability of regular green and/or black tea consumption to decrease oxidative stress during the context of a randomized, controlled, double blinded, dietary intervention trial. Testing for biomarkers of oxidative stress in EBC might complement other innovative methods currently being investigated. The use of this novel strategy might enable further classification of people at risk of increased oxidative stress lung cancer, such as smokers, workers in nuclear weapons plants, Gulf War veterans, and US Marines by degree of risk. Such refinement of risk analysis might then be used to identify candidates for screening studies.