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Am J Physiol Lung Cell Mol Physiol 280: L755-L761, 2001;
1040-0605/01 $5.00
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Vol. 280, Issue 4, L755-L761, April 2001

Reduction of BCNU toxicity to lung cells by high-level expression of O6-methylguanine-DNA methyltransferase

Min Wu1, Mark R. Kelley2, W. Kent Hansen2, and William J. Martin II1

1 Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Internal Medicine, and 2 Department of Pediatrics and Biochemistry and Molecular Biology, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is an important cause of pulmonary toxicity. BCNU alkylates DNA at the O6 position of guanine. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl groups from the O6 position of guanine. To determine whether overexpression of MGMT in a lung cell reduces BCNU toxicity, the MGMT gene was transfected into A549 cells, a lung epithelial cell line. Transfected A549 cell populations demonstrated high levels of MGMT RNA, MGMT protein, and DNA repair activity. The overexpression of MGMT in lung epithelial cells provided protection from the cytotoxic effects of BCNU. Control A549 cells incubated with 100 µM BCNU had a cell survival rate of 12.5 ± 1.2%; however, A549 cells overexpressing MGMT had a survival rate of 71.8 ± 2.7% (P < 0.001). We also demonstrated successful transfection of MGMT into human pulmonary artery endothelial cells and a primary culture of rat type II alveolar epithelial cells with overexpression of MGMT, resulting in significant protection from BCNU toxicity. These data suggest that overexpression of DNA repair proteins such as MGMT in lung cells may protect the lung cells from cytotoxic effects of cancer chemotherapy drugs such as BCNU.

overexpression; DNA repair protein; interstrand cross-link; alkylation; 1,3-bis(2-chloroethyl)-1-nitrosourea


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