) Although there is substantial epidemiological and experimental evidence of a protective effect of a high intake of fruits and vegetables against lung cancer (LC), studies that have attempted to isolate specific nutrient effects have given variable results. One possible reason for the lack of consistency between studies of individual nutrients and fruits and vegetables is that the frequently studied components like beta-carotene and other antioxidants in fruits and vegetables may not be the only protective components. We advance the possibility that folate in fruits and vegetables is one of these relatively unstudied components. The potential mechanisms whereby deficiencies of folate and inter-related vitamin B-12, could lead to gene damage via DNA hypomethylation are well understood. Furthermore, chemical components of cigarette smoke have been shown to interact with folate and vitamin B-12, transforming them into biologically inactive compounds. That these chemical reactions may have physiologic significance is supported by the reports of lower circulating and buccal mucosal folate levels in smokers, and a response of bronchial metaplasia to folate/B-12 supplementation. We expect the effect of smoking to be greatest in the lung, where the potential for cigarette smoke to oxidize and destroy micronutrients should be most pronounced. Yet, the importance of folate and vitamin B-12 in LC prevention is not widely appreciated. There are no reports on the measurement of folate or vitamin B-12 levels in lung tissue. Although there are some reports on the epithelial lining fluid (ELF) levels of vitamins C and E, and their accumulation by alveolar macrophages (AM) of smokers, none of these studies has measured a battery of vitamins in the same sample, studied the significance of AM accumulation of vitamins, or most importantly, correlated those vitamins with the expression of intermediate endpoint biomarkers (IEB). The identification of IEB in LC has proceeded briskly, but studies of the chronology of early events are only in their infancy. Therefore, special emphasis will be given to the identification and validation of IEB in lung carcinogenesis since this is an inadequately documented but emerging area in cancer prevention research. This five-year Preventive Oncology Academic Award will provide the applicant with intensive training in IEB research under expert guidance to become an independent researcher in this area. Following this, the dietary intake and concentrations of folate, vitamins B-12, A, E, C, and beta-carotene in ELF, AM, bronchial biopsies, and blood will be measured along with global DNA hypomethylation and IEB in bronchial biopsies of smokers and non smokers matched for age, gender, and race. Along with identifying and validating IEB, the proposed studies will provide insight into the mechanisms for the well-documented protective effects of fruits, vegetables, and antioxidant nutrients on the risk for lung cancer in smokers, and will provide much needed base-line data for the evaluation of chemopreventive applications of vitamins. These activities, along with advanced studies of epidemiology and statistical analysis and experience in teaching, will provide the expertise needed for a career as a successful, independent investigator.
