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

Min Wu, Mark R. Kelley, W. Kent Hansen, William J. Martin

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L755-L761
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume280
Issue number4 24-4
DOIs
StatePublished - Apr 2001

Keywords

  • 1,3-Bis(2-chloroethyl)-1-nitrosourea
  • Alkylation
  • DNA repair protein
  • Interstrand cross-link
  • Overexpression

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Reduction of BCNU toxicity to lung cells by high-level expression of O<sup>6</sup>-methylguanine-DNA methyltransferase'. Together they form a unique fingerprint.

  • Cite this