1178

More than 80% of lung cancers are caused by cigarette smoking. Cigarette smokers inhale a broad range of carcinogens derived from tobacco and its pyrolysis products, which can induce formation of DNA adducts in lungs. It has been shown that the levels of carcinogen DNA adducts in tumor tissues from current smokers were significantly lower compared to those from the corresponding adjacent normal tissues. Several major factors including structural DNA alterations, presumably contribute to the decreased levels of carcinogen DNA adducts in the tumor tissues. In order to understand the mechanisms, several experiments were carried out. First, we have analyzed levels of DNA adducts in primary non-small cell lung cancer (NSCLC) tissues and corresponding adjacent normal lung tissues from 18 patients (8 current smokers, 6 former smokers, and 4 nonsmokers). Levels of DNA adducts including the diagonal radioactive zone (DRZ) in the adjacent normal lung tissues from current smokers were higher than those from the corresponding tumor tissues with total RAL x 109 values (Mean ± SEM) being 75.01 ± 14.23 and 22.61 ± 1.27, respectively (P=0.003). Second, DNA samples isolated from lung tumor and adjacent tissues of 4 individual patients were incubated with 10 μM benzo(a)pyrene (BaP) and 3-methylcholanthrene-induced liver microsomes in the presence of NADPH, and BaP-DNA adducts were measured. DNA from adjacent tissues displayed higher levels of adducts compared to those from tumor tissues with total RAL x 107 values (Mean ± SEM) being 153.29 ± 5.64 and 115.70 ± 25.70, respectively (P=0.11). Major DNA adducts from in vivo and in vitro experiments were identical. Third, dose-response experiment in which human lung DNA was treated with 0.125, 0.25, 0.50, and 1.0 μM BaP with microsomes, also showed about 20% higher of adduct levels in normal DNA than tumor DNA. Furthermore, five different sequences of oligonucleotides were incubated with BaP, microsomes and NADPH. The oligonucleotides with GCG sequence yielded much higher levels of DNA adducts compared to oligonucleotides with GAG, AA, AG, TC, and CT sequences. These results suggest that DNA sequence alterations, presumably arising out of DNA mutations, are one of the major factors that contribute to the significantly decreased levels of carcinogen DNA adducts in tumor tissues. Moreover, our observations demonstrate that DNA adducts may serve not only as sensitive biomarkers in carcinogenesis and cancer prevention studies, but also are helpful to further our understanding of the mechanisms of carcinogenesis. (Supported by P30-ES09106 and P01-CA91844).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]