June 15, 2004

COX-2 Enzymes Modulate DNA Damage
in Cells
Study Provides Insights Into COX-2 Inhibitors’ Cancer-Preventing Abilities

(Boston, MA) - In an ongoing effort to understand the link between oxidative stress and cancer, Ian Blair, PhD, Director of the Center for Cancer Pharmacology at the University of Pennsylvania School of Medicine, and colleagues have discovered the first evidence in cells that cyclooxygenase-2 enzymes (COX-2) can cause DNA damage and that the inhibition of that damage may be important in preventing cancer. Blair will report these findings at the annual meeting of the American Society for Biochemistry and Molecular Biology (ASBMB)/8th International Union of Biochemistry and Molecular Biology Conference in Boston. He will participate in a press briefing at the meeting starting at 11:00 EST, Tuesday June 15.

Using cells transfected with COX-2 developed at Vanderbilt University, Blair and his team showed that COX-2 can cause DNA damage. “This now makes the link between cyclooxygenases, lipid hydroperoxides, and DNA damage,” says Blair. During oxidative stress, lipids are oxidized to form molecules called lipid hydroperoxides, which in turn degrade to highly reactive compounds called genotoxins. These genotoxins bind to DNA and cause mutations. A number of studies are ongoing in Blair’s and other labs to look at the effect of COX-2 inhibitors on cancerous cell growth. COX-2 inhibitors are now the basis of such pain and inflammation medications as Vioxx and Celebrex.

In a previous study, Blair and his lab found that vitamin C, an antioxidant, can increase the formation of genotoxins resulting from the oxidation of lipids. In this present study, they showed that this activity also occurs in cells.

Under normal conditions, lipid hydroperoxides break down so quickly that they never degrade into genotoxins. But during oxidative stress -- when natural antioxidants within the body fail to mop up damaging molecules -- genotoxins build up and cause DNA damage. Genotoxins chemically bond to DNA, thereby changing its structure. When DNA is being replicated the resulting mutations cause widespread mistakes in the production of proteins and cell death.

Genotoxins carry the effect of a double-edged sword. “In the case of chemotherapy when a genotoxin binds to DNA, the cell signals for that tumor cell to die,” explains Blair. But genotoxins can have deleterious effects in that they also cause mutations in normal cells.

A new method for the analysis of DNA damage in these cells was developed by Seon Hwa Lee, a Research Associate in Pharmacology, and Michelle Williams, a student in the Graduate Group in Pharmacological Sciences.

This work points to another way to prevent cancer-drugs that remove COX-2-associated genotoxins. Many studies have shown that diets high in fruits, grains, and vegetables may reduce cancer risk, and now Blair’s group is looking for micronutrients in these foods that are able to remove COX-2 genotoxins. “There are many levels at which you can protect against DNA damage,” says Blair. “What our work has done is to focus attention on the fact that it’s not just a single magic bullet, that a good diet is better than just taking loads of vitamin pills.”

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