Study Finds First Evidence COX-2 Enzymes Can Regulate DNA Damage

From: JWissmille (jwissmille_at_aol.com)
Date: 06/23/04 

Date: 23 Jun 2004 01:00:35 GMT

http://news.biocompare.com/newsstory.asp?id=41457

Study Finds First Evidence COX-2 Enzymes Can Regulate DNA Damage
6/15/2004
Source: Federation of American Societies for Experimental Biology

Scientists from the University of Pennsylvania's Center for Cancer Pharmacology
report the first evidence that cylcooxygenase-2 enzymes (known as COX-2) are
not only responsible for pain and inflammation but that they are also involved
in causing the DNA damage associated with cancer.

Dr. Ian Blair reports this study for the first time on June 15th at the Annual
Meeting of the American Society for Biochemistry and Molecular Biology
(ASBMB)/8th International Union of Biochemistry and Molecular Biology
Conference (IUBMB) in Boston. His research team's discovery casts a new light
on the mechanism through which aspirin - and diets rich in fruits, grain and
vegetables -- appear to lower the risk of some cancers. It also suggests a
potential role for the widely used COX-2 inhibitors in the prevention of DNA
damage.

In the same presentation, Dr. Blair reports new data that support his earlier
discovery that vitamin C can increase DNA damage. His 2001 article in Science
was the first to report a potential negative effect of vitamin C and thus
caused a firestorm of attention, although Dr. Blair was careful to spell out
that he believed that in order to be at risk for DNA damage from vitamin C an
individual would have to take some unknown high quantity of the vitamin,
experience oxidative stress, and have a problem with the ordinarily efficient
DNA repair enzymes. The two studies are closely related, says Dr. Blair,
because the COX-2 enzyme produces lipid hydroperoxides and vitamin C stimulates
their breakdown. This results in the formation of a class of DNA-harming agents
called genotoxins, which are known to be involved in the formation of certain
human cancers.

Interest in the potential use of COX-2 inhibitors as anticancer agents was
fueled in part a decade ago when an American Cancer Society study showed that
regular use of aspirin led to an unexpectedly low incidence of colon cancer..
But all was not rosy. In addition to inhibiting the production of COX-2,
aspirin also inhibits production of COX-1. These COX-1 enzymes make
prostaglandins, regulatory molecules important for, among other things,
preventing the formation of ulcers in the gastrointestinal tract.

But what if the culprit in the creation of genotoxins, and thus the real target
of aspirin in preventing cancer, had nothing to do with prostaglandins and
instead was actually some other product derived from COX-2? Ten years ago
researchers at Vanderbilt Universitydemonstrated that COX-2 was present in
colon tumors but not in surrounding healthy tissues. The Vanderbilt laboratory
then developed a cellular model that introduced the COX-2 enzyme into cells to
study the biochemical changes that occurred. In a spirit of scientific
collegiality, the Vanderbilt group supplied Dr. Blair's lab their cellular
model so that the University of Pennsylvania team could look at whether the
COX-2 enzyme could produce the DNA-damaging genotoxins that the COX-1 enzyme
was unable to make.

A new method was developed for the analysis of DNA damage in these cells at the
University of Pennsylvania by Dr. Seon Hwa Lee, Research Associate in
Pharmacology, and Ms. Michelle Williams, a student in the Graduate Group in
Pharmacological Sciences. They found that in the cells COX-2 was able to make
lipid hydroperoxides and that vitamin C could efficiently convert them into
genotoxins.

Under normal circumstances, says Dr. Blair, oxidized hydroperoxide is rapidly
removed from the cells before it would have time to degrade into genotoxins but
under abnormal circumstances such as oxidative stress, degradation could take
place.

Dr. Blair says these studies provide the first hint that COX-2 enzymes are
responsible for DNA damage and that inhibition of this damage may be important
for preventing cancer. He believes that the ability of COX-2 inhibitors to
prevent genotoxin formation during cellular oxidative stress suggests a
potential usefulness in cancer prevention and that new drugs could be developed
to remove COX-2 derived cellular genotoxins.

###

Contact: Sarah Goodwin
asbmb04@bellsouth.net
770-270-0989
Federation of American Societies for Experimental Biology

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