CARCINOGEN DOSIMETRY AND ONCOGENE ACTIVATION

We propose to conduct 3 related pilot studies in humans aimed at further validating various markers of carcinogen-DNA interaction as dosimeters for the "biologically effective dose" of carcinogens and as potential markers of elevated risk. A secondary goal is to carry out a preliminary investigation of the phenomenon of activated oncogenes and its possible relationship to evidence of carcinogen-DNA interaction in the same tissue. In this regard, we will also correlate activation of oncogenes with exposure history and histopathological and clinical features of cancer. Specifically, we will investigate the relationship between 2 chemical-specific immunoassays (benzo(a)pyrene (BaP)-DNA binding, BaP-protein binding) and a generic dosimeter (sister chromatid exchange or SCE) in individuals with detailed exposure histories. Results in the assays will be correlated with data obtained by questionnaire regarding exposure to BaP, to other mutagens/carcinogens associated with SCEs and to a limited number of agents believed to modify carcinogen metabolism in humans. Our study subjects will be drawn from 3 groups: smokers/nonsmokers, coke oven workers/controls, and lung cancer patients/orthopedic controls. Measurements of BaP adducts in DNA extracted from leukocytes and of SCEs in lymphocytes will be compared with levels of BaP-hemoglobin binding in red blood cells of all study subjects except, of course, autopsy controls. In addition, DNA from the tumors and normal lung tissue of lung cancer patients and normal lung tissue from autopsy controls will also be assayed for BaP adducts and for evidence of activated oncogenes. We will compare the two groups (patients and controls) asking whether, when exposure is comparable, lung cancer patients have higher levels of markers suggesting a greater inherent susceptibility to carcinogens. The study, although complex, is cost effective in that we will be able to take advantage of an ongoing, concurrent investigation of the relationship between BaP-DNA binding and exposure to BaP via smoking, occupation, diet, etc. in these same populations. These parallel observational and clinical studies using the same protocols are intended to develop meaningful data on the potential usefulness of new methods in human monitoring and carcinogenic risk assessment.