Antioxidant Enzyme Genes and Oxidative DNA Damage Repair Genes: Potential Biomarkers for the Early Detection of Lung Cancer

Reactive oxygen species (ROS) are produced in cells by both endogenous and exogenous processes. Oxidative stress arises when the ROS are at high enough concentrations to overwhelm the cell's normal antioxidant defense mechanisms. The fact that DNA is modified by ROS has led to the suggestion that oxidative stress may be an important factor in the process of carcinogenesis. Mammalian cells contain three main antioxidant enzymes that function to maintain ROS at very low concentrations. Catalase (CAT) acts to scavenge hydrogen peroxide. Glutathione peroxidase (GPX) detoxifies hydrogen peroxide as well as lipid-derived organic hydroperoxides. Superoxide dismutase (SOD) converts the superoxide anion radical to hydrogen peroxide. Decreased expression of CAT, GPX and SOD in cancer cells would be expected to result in elevated levels of hydrogen peroxide and superoxide. A number of studies have shown that the activities of these enzymes are decreased in tumor cells compared to adjacent normal tissue. Downregulation of antioxidant gene expression results in consistently elevated levels of ROS, a state referred to as persistent oxidative stress. ROS cause several types of DNA damage, including base modification, strand breakage, and DNA-protein cross-links. One of the major oxidatively modified DNA bases in vivo is 8-hydroxy-2'-deoxyguanosine. This product, which is also referred to as 8-OH-dG or 7,8-dihydro-8-oxo-2'-deoxyguanosine, is mutation prone and results in a G:C to T:A transversion following DNA replication. Elevated levels of 8-OH-dG have been detected in cancers from several tissues (i.e., breast, lung and kidney). Human mutT homologue (hMTHl) prevents the formation of 8-OH-dG residues by dephosphorylating 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing misincorporation of the oxidized free nucleotide into DNA. Overexpression of hMTHl mRNA has been detected in primary renal cell and breast carcinomas as well as in lung cancer cell lines. Human 8-oxoguamne DNA glycosylase (hOGGl)catalyzes the excision of 8-oxo-guanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamido-pyrimidine (Fapy) from DNA. To date, no studies have shown hOGGl to be overexpressed in tumor tissues. However, expression of hOGGI has been shown to be upregulated in vitro in response to oxidative stress. Human mutY homologue (hMYH) has an enzymatic activity that removes an adenine base from an A:8-oxoG base pair. No studies have examined the expression of hMYH in tumor tissues. If persistent oxidative stress is a feature of cancer cells, then it is predicted that hMTHl, hOGGl and hMYH should be overexpressed in these cells. By measuring protein levels of CAT, GPX, SOD, hMTHl, hOGGl and hMYH in sputum samples from at-risk individuals (i.e., smokers), it should be possible to detect persistent oxidative stress in exfoliated cells from the lung. This may provide a new strategy for the early detection of lung cancer.Master of Public Healt