DNA REPAIR MEASURES AS BIOMARKERS FOR CANCER PREVENTION

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This resubmission sets forth a scientific problem: to develop a coherent framework into which to rationally fit both current biochemical and epidemiologic findings so as to impact on cancer prevention efforts in the general population. The strong interactions among the Principal Investigator, the Institution, and her sponsors make this an ideal project for the research and training components of the KO-7 Award. The major focus of this proposal is on the role of anti-oxidants and enzymes with DNA repair capacity, in order to gain insight into their relationships and, possibly, the mechanism of carcinogenesis. Free radicals have been imputed in carcinogenesis. Active oxygen species as well as other oxygen-centered free radicals may act as tumor initiators or promoters, or both. In preliminary case-control comparisons, adenosine diphosphate ribosyl transferase (ADPRT) and related enzymatic measures of DNA repair have shown strong associations with lung cancer as well as colon cancer, colorectal polyps, and breast cancer. Two epidemiologic studies are proposed: (1) a case-control study and (2) a feasibility study for a larger, prospective cohort study. The primary aim of the two epidemiologic studies proposed is to test the hypothesis that cancer is associated with measures of DNA repair capacity, ADPRT, UDS, O6-MGT, and cancer status, while controlling for anti-oxidant micronutrients, Beta-carotene, alpha-tocopherol, and ascorbic acid. A second major aim is to test the associations of the antioxidants to the measures of ADPRT, UDS, and O6-MGT in two ways: (i) by dietary questionnaire and (ii) by plasma assay. Finally, this proposal contains a feasibility study for a prospective cohort study which will examine these associations prospectively in order to test their ability to predict cancer and to provide a population in which to test interventions to prevent cancer. The objectives of the feasibility study are to (a) define recruitment procedures, (b) develop intervention approaches, and (c) establish systems to measure cancer incidence prospectively in this population. The training program set forth support the candidate in making the transition from field epidemiology biochemical and molecular epidemiology through an tailored program of coursework, seminars, consultation and mento hip. Throughout the proposal, we have addressed the concerns of the reviewers. Specifically, we have itemized their criticisms in the Introduction to the Scientific Section (page 16). The issue of causality is addressed as well as clarification of the time commitments and the rationale for sampling lung tissue.