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Studies show powerful natural
anti-cancer system exists
BALTIMORE -- Mar. 13, 2001 -- Scientists have
confirmed the existence of the body's long-suspected natural
system for blocking the cancer-causing effects of toxic chemicals
in food and the environment.
In two separate studies, researcher at Johns
Hopkins Medical Center and Tsukuba University in Japan found
that a sharp boost in protective enzymes, called phase II enzymes,
can dispose of toxic chemicals by effectively neutralizing their
ability to damage DNA and trigger cancer.
Writing in the current Proceedings of the
National Academy of Sciences, Dr. Paul Talalay, a molecular
pharmacologist at Hopkins, says the work not only demonstrates
the fundamental workings of the system, but also pinpoints the
key "switch" that regulates it.
"We've gained long-awaited proof of a
basic mechanism that can reduce the risk of cancer," Talaly
said in a prepared statement.
Scientists already know that natural substances
in plants, such as the sulforaphane in broccoli, as well as some
man-made chemicals, can tap into this system -- that they're
somehow "chemoprotective" -- but the route hasn't been
clear.
The new work, a result of 20 years' research,
"confirms that raising the levels of phase II enzymes can
offer a highly effective way to achieve protection against carcinogenesis,"
says Talalay. "We always had faith, now in our animal studies,
we have a direct demonstration."
In one study, the scientists knocked out a
gene that produced a protein called Nrf2 in genetically engineered
mice and saw the activity of phase II enzymes drop dramatically
compared with mice whose "switch gene" was intact.
The second study shows that the levels of
these enzymes are tightly controlled by the cellular equivalent
of a dimmer switch, says Dr. Thomas Kensler, a toxicologist at
Hopkins.
"Our precise understanding of this system
should make it fairly easy to design drugs that can fine-tune
it," says Kensler who is now overseeing early clinical trials
of one such drug in China. "We have evidence that we can
increase the system's levels of protection in people and are
planning long-term studies that would reveal any lowered incidence
of cancer."
When they exposed both the knockout mice and
normal mice to benzpyrene, a potent carcinogen in cigarette smoke,
both developed tumors, but the knockouts, which were apparently
disconnected from the protective system, had significantly more.
In a more telling demonstration of the system,
the scientists gave both the normal and the knockout mice a drug
called oltipraz along with the benzpyrene carcinogen. Oltipraz
has been used for parasite infections. But it was also shown
in earlier Hopkins studies to raise levels of phase II enzymes
and lower cancer risk.
Dr. Masayuki Yamamoto, a molecular biologist
at Tsukuba Univeristy in Japan, showed that carcinogen-exposed
normal mice on oltipraz had their tumor number cut by half. But
the knockout mice were tumor-ridden, even with the protective
drug.
"This shows the great importance of the
Nrf2 'switch.'Without it, the mice couldn't be protected says
Yamamoto."
Earlier work by Yamamoto showed that protective
chemicals, such as those in plants, work by sparking cells' release
of Nrf2. Then Nrf2 activates a common DNA sequence on the genes
of all phase II enzymes, switching them on.
"Scientists have tried to learn what
makes some people more susceptible to cancer," Kensler adds.
"They've looked at genes for single phase II enzymes here
and there. But with NRf2, you have the control for all of them.
With slight changes in the 'switch,' you can get a tremendous
step up in a body's sensitivity to cancer agents."
Turning the system up or down might have value,
says Yamamoto. "By turning down an organism's ability to
squelch carcinogens, you could get an exquisitely sensitive model
for testing, say, which pollutants in the Chesapeake Bay cause
tumors to form. Likewise, you could turn it up and, in theory,
increase any animal's resistance to cancer or, perhaps, other
diseases."
The researchers believe the system is a common,
general one in many animals. "Also," says Kensler,
"we think it may be part of a broader way animals deal with
many types of toxicity not just carcinogens. Toxicity plays a
role in many conditions such as atherosclerosis and neurodegenerative
diseases."
SOURCE: Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 6,
3404-3409, March 13, 2001
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