A
NEW APPROACH TO THE WAR ON CANCER has caught the interest of a
growing group of scientists: Increase consumption of compounds that reduce
genetic damage and other cancer-promoting processes, and patients can
decrease the chance that tumors will ever develop.
The strategy, known as chemoprevention, is only about 20
years old. New leads for chemoprevention treatments sometimes come from
traditional medicine, so it’s easy to confuse chemoprevention with
the vague promises of better health attached for centuries to maternal
calls of “Eat your vegetables!”
Ming You, MD, PhD, professor of surgery, is determined to
convince both the general public and other faculty members at the School
of Medicine that not only is chemoprevention a hard science, it’s
a field in which the potential benefits are well worth pursuing.
“This is a far cry from people saying, ‘If you
just eat healthy, you maybe will have less disease for the next 20 years,’”
You says. “It’s a new idea that these kinds of dietary alterations
can have quantifiable medical effects, but they lead to predictable outcomes.
You can actually calculate how many cancer cases you can cut per hospital.”
Yian Wang, MD, PhD, and Ming You, MD, PhD, are evaluating
a host of substances derived from foods and other sources for their potential
benefit in preventing cancer.
CHEMOPREVENTIVE AGENTS IN THE
NEWS have included tamoxifen, a substance derived from yew trees
that can reduce the risk of breast cancer, and broccoli sprouts, which
contain a compound that promotes production of enzymes that prevent harm
to DNA.
You thinks that Washington University has the resources
to make it an international leader in the development of chemopreventive
agents.
“The university has a tradition of excellence in many
areas, but chemoprevention certainly isn’t one of them yet,”
says You. “We have everything we need, in terms of the extensive
cancer expertise here at the Siteman Cancer Center, the basic and clinical
research expertise throughout the university, and our connections to institutions
like the Missouri Botanical Garden and the Donald Danforth Plant Science
Center. But the interest in chemoprevention just isn’t here yet.”
You, who has an obvious gift for confronting discouraging
odds with near-manic energy and contagious cheerfulness, came to the school
last year with Yian Wang, MD, PhD, associate professor of surgery. You
and Wang (who are married) are both actively involved in chemoprevention
research, and You has made it a priority to generate interest in chemoprevention
among other Washington University faculty. He uses several scenarios to
make the pitch for chemoprevention; the first comes from his research
specialty, lung cancer.
“In the last few years, we have had millions of people
who listened to all the information about stopping smoking and managed
to stop,” explains You. “But they may then hear that they
still have a significant risk of lung cancer.”
Cancer risk decreases after quitting, but only very slowly
and incrementally. Thanks to the success of anti-smoking initiatives,
doctors actually now see more former smokers who are first-time lung cancer
patients than they do current smokers. Add this to the fact that lung
cancer brings a nearly 90 percent chance of dying within three years,
and many are eager to find new ways of reducing risk.
“Lung cancer is the number one cancer killer of both
men and women,” he says. “If we could find a chemopreventive
agent that cuts the risk of lung cancer by 50 percent, that would save
nearly 100,000 lives a year.”
Another scenario You describes centers on the identification
of several genes that can increase the risk of developing various types
of cancer. You and Wang,
frequent research collaborators, both do research into genes
that increase risk of cancer.
Physicians can test patients for these genetic factors, but ideally would
also like to be able to give them a chemopreventive agent that can help
bring high risk levels down.
Wang, who works with a rat model to study genetic factors
linked to breast tumors, recently had encouraging results in an attempt
to block mammary tumors that normally develop in response to a carcinogen.
“We’ve been seeing some promising preventive
effects in trials of retinoids, synthetic compounds that mimic some of
the properties of vitamin A,” she says.
The final scenario is a patient with a precancerous lesion.
According to You, it may be possible to develop chemopreventive agents
that not only help push a precancerous growth back into normalcy but also
help decrease the chances that such growths will develop again.
You emphasizes that chemoprevention doesn’t guarantee
a way to completely beat the odds but instead provides a method for tilting
them in a patient’s favor.
“We have a goal of maximum efficacy with minimal harm,
so I don’t think this approach is likely to ever prevent 100 percent
of cancers,” You explains. “Chemoprevention is not like chemotherapy,
where the number one concern is prolonging life at any cost. Many of the
patients we hope to treat don’t have cancer yet, they just have
a high risk. So they don’t want to lose hair or their appetite—they
want to live normally and still prevent cancer from occurring.”
Finding new leads for potential chemopreventive agents often
involves an odd mixture of investigating folk remedies and applying the
latest basic research into the origins of cancers.
You describes the work of John Pezzuto, dean of the School
of Pharmacy at Purdue University, as an example. The famous contrast between
traditional high-fat diets in Mediterranean countries and the low rates
of cancer and heart disease found in those areas led him to study the
grapes that went into the region’s red wines. He found a potent
anti-cancer compound called resveratrol in the skins of the grapes.
You places his laboratory halfway along the chain of development
from lead to treatment. He doesn’t screen dozens of potential chemopreventives
— “they’re about 90 percent wrong and 10 percent gold,”
he says—but instead tests the best leads in animals and isolates
the compounds providing the chemopreventive effect. His team lays the
groundwork on preclinical studies that make human clinical trials possible
for other, more clinically oriented research groups.
You’s lab has helped to advance two promising members
of a new generation of potential lung tumor preventives. He and Stephen
Lam, a pulmonologist at the University of British Columbia in Vancouver,
have been working with an herbal tea mixture that a Chinese doctor, Lin
Pei-Zhong, showed could reduce the rates of esophageal cancers.
“I’m normally very suspicious of herbal mixtures,
but he presented solid scientific data at a conference in China in 1996
and was willing to let us work with him,” says You, who now has
a paper in the works confirming the mixture’s anti-tumor effects
in mice.
Lam and You also are co-principal investigators on a clinical
trial to see if green tea can reduce the occurrence of lung cancer. The
trial is currently underway at the University of British Columbia’s
Cancer Centre.
YOU HAS MADE PROGRESS VERY
RECENTLY in his efforts to interest Washington University faculty
in chemo-prevention. He and Lynn A. Cornelius, MD, associate professor
of medicine and head of the division of dermatology, are seeking funds
to test chemopreventive agents in solid organ transplant recipients.
Transplant patients have to take immuno-suppressive drugs
to prevent rejection of their new organs, but because the immune system
also plays a role in fighting cancer, those drugs can combine with other
factors to greatly increase the patient’s risk of skin cancers.
Dermatologists estimate that transplant patients may have 64 times the
normal risk for squamous cell cancer, 10 times the risk for basal cell
cancer, and three times the risk for malignant melanoma.
“This has been a significant problem in the management
of these patients, particularly those who are fair-skinned and have had
considerable sun exposure,” says Cornelius. “This is a perfect
patient population at risk for skin cancer in which to develop chemopreventive
therapies.”
Physicians currently use compounds related to vitamin A
to lower cancer risk, but they have serious disadvantages. Working with
Daniel C. Brennan, MD, associate professor of medicine and director of
the renal transplant service, Cornelius had been considering the possibilities
of trying a green tea extract or omega-3 fatty acids as chemoprevention
therapies. That’s when Brian Springer, research administrator at
the Siteman Cancer Center, put Cornelius in touch with You.
“I am totally impressed with Dr. You’s enthusiasm
and knowledge regarding chemoprevention, along with his willingness to
help formulate an approach for a clinical intervention,” says Cornelius.
You hopes that Cornelius will be the first of many faculty
he can assist with chemoprevention research.
“Chemopreventive agents are starting to happen for
breast cancer, they’re rapidly becoming available for colon cancer,
and there are even some new leads for prostate cancer,” he says.
“Things are starting to happen very quickly.”
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