June 15, 2004
COX-2 Enzymes Modulate DNA Damage
Study Provides Insights Into COX-2 Inhibitors’
(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
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
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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