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Decreased Repair Activities of 1,N⁶-Ethenoadenine and 3,N⁴-Ethenocytosine in Lung Adenocarcinoma Patients¹

Elbieta Speina, Maja Zieliska, Alain Barbin, Daniel Gackowski, Janusz Kowalewski, Maria A. Graziewicz, Janusz A. Siedlecki, Ryszard Oliski and Barbara Tudek²

Department of Molecular Biology, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawiskiego 5a, 02-106 Warsaw, Poland [E. S., M. Z., M. A. G., B. T.]; International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France [A. B.]; Department of Clinical Biochemistry [D. G., R. O.] and Department and Clinic of Thoracic Surgery and Tumours [J. K.], The Ludwik Rydygier Medical University in Bydgoszcz, Karowicza 24, 85-092 Bydgoszcz, Poland; and Department of Molecular Biology, Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland [J. A. S.]

To assess the role of oxidative stress and lipid peroxidation (LPO) in the pathogenesis of lung cancer, we measured the levels of 1,N⁶-ethenoadenine (A) and 3,N⁴-ethenocytosine (C) in the DNA by immunoaffinity/³²P postlabeling (33 cases). We also measured the capacity for A and C repair (by the nicking assay) in normal and tumor lung tissues, as well as in blood leukocytes of lung cancer patients (56 cases). Repair activities for A and C were also assayed in leukocytes of healthy volunteers, matched with cancer patients for age, sex, and smoking habit (25 individuals).

Up to 10-fold variations among individuals were observed both in adducts level and repair activities. No differences in A and C levels between tumor and nonaffected lung tissues were recorded. However, leukocytes accumulated a significantly higher number of DNA adducts than the lung tissues. Repair activities for both A and C were significantly higher in tumor than in normal lung tissue. No significant differences in A and C repair activities were associated with age, sex, or smoking habit. However, a significant difference in repair capacity was observed between two histological types of lung cancer, squamous cell carcinoma (SQ) and adenocarcinoma (AD). In individuals suffering from lung AD, A- and C-repair activities in normal lung and blood leukocytes were significantly lower than in SQ patients. Moreover, in nonaffected lung tissue of AD patients, the ratio A/C adducts was lower than in SQ patients. Differences have also been found between A and C repair activities of cancer patients and healthy volunteers. Repair capacity for A was significantly lower in blood leukocytes of lung cancer patients than in leukocytes of healthy volunteers (P = 0.012). This difference was even larger between healthy volunteers and patients developing inflammation-related AD (P = 0.00033). Repair activities for C were the same in leukocytes of healthy controls, all lung cancer patients, and SQ patients. However, individuals with ADs revealed significantly lower C-repair activity (P = 0.013).

These results suggest that oxidative stress-mediated lipid peroxidation might contribute to induction and/or progression of lung cancer. Decreased activity of base excision repair pathway for A and C is associated particularly with inflammation-related lung AD.

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