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A Publication of the James Buchanan Brady
Urological Institute Johns Hopkins Medical Institutions
Volume V, Winter 2000
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PROSTATE CANCER AND DIET
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Bill Nelson:
a pioneer in the study of diet as preventive medicine, is looking for foods
or nutrients that boost disease-fighting enzimes, and help the body ward of prostate cancer.
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Imagine you are watching an old movie Western, and here comes the hero: You know him instantly -- he's clean-cut,
wit broad shoulders and a white hat, riding tall in the saddle on a fine white horse. But then the unthinkable happens:
His big fight scene with the villain is over almost before it starts.
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The disappointing hero is a crucial enzyme called glutathione-S transferase p, the venue is the prostate,
and the chaos that results from the enzyme's failure to do its job -- which is to protect DNA from outside forces that can harm it
-- eventually leads to prostate cancer.
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An Evolutionary Wrong Turn |
One punch and he's down for the count.This hero has a glass jaw; in fact, he's the most ineffective "good guy" you ever saw. As a champion he's a dud.
Oncologist Bill Nelson, M.D., Ph.D. has seen this drama many times before, played out on a tiny stage. The
disappointing hero is a crucial enzyme called glutathione-S transferase p (pronounced "Pi"), the venue is the
prostate, and the chaos that results from the enzyme's failure to do its job -- which is to protect DNA from outside
forces that can harm it -- eventually leads to prostate cancer.
Nelson was the first to figure out glutathione-S transferase p's role in prostate cancer. If cancer is a chain reaction--
on genetic mistake, or mutation, that leads another, and so on -- then what happens to this hapless enzyme, he
believes, is probably among the very earliest events. One or more genetic "bad guys" -- outside factors that cause the
body's defenses to break down, most likely related to a mar lifetime diet -- attacks glutathione-S transferase. Like our
poor hero in the movie the enzyme -- apparently all that stands in the way of prostate cells and potentially toxic agents --
doesn't put up much of a fight. Eliminating glutathione-S transferase p makes prostate cells
vulnerable to cancer
because it strips them of their bodyguard. Without this cancer-fighting enzyme, cells are far less able to detoxify
carcinogens.
Several years ago, Nelson began to wonder: If glutathione-S transferase p can be knocked out by bad environmental
agents can the reverse happen? Can it also be stimulated? Is there some dietary equivalent to Charles Atlas that
can build up the scrawny hero before it's too late, so it can fend for itself -- and perhaps deter prostate cancer? In
other words, is it possible to use food, or some particular nutrient, as preventive medicine?
Nelson, a pioneer in this area, is not alone: All over the world, scientists in many disciplines are studying diet as
never before -- for the first time, trying to under stand exactly how specific foods work in the body, right down to
which particular enzymes (like glutathione-S transferase p ) are helped or hurt by what we
eat and drink.
Beta
Carotene: A Cautionary Tale
It seems increasingly obvious that, from a health standpoint,
the rich Western dietnotoriously high in animal fats and poor in grains,
fruits and vegetables -- leaves a lot to be desired. (See
"The Western Dilemma") But where's the
smoking gun, the cancer instigator? Is it something we eat too much of,
or something we routinely omit from our meals?
"It's harder to pin down than you might think," says Nelson, who is troubled by the recent flurry of interest --
misplaced, it seems -- in beta carotene for prevention of lung cancer. A few years ago, in several case-controlled
studies, scientists noticed that smokers who ate a lot of fruits and vegetables seemed to be protected against lung
cancer. What, in particular, was it about fruits and vegetables that warded off cancer? The scientists honed in on
beta carotene, a nutrient that's rich in vegetables. They wondered if beta carotene could be a biomarker -- a sort of
barometer in the bloodstream -- hypothesizing that people with high levels of beta carotene would have a lower risk of
lung cancer. Sure enough, in early studies with lab animals, beta carotene performed like a champ, seeming to
protect against several kinds of cancers. Suddenly, beta carotene was the hot new scientific flavor of the month.
"There was practically an intergalactic consensus that beta carotene must be good for you," says Neison. "As a
result, not just one but three separate beta carotene supplementation trials were initiated. To make a long story
short, all of them showed not only that beta carotene did not do what it was predicted to do and prevent lung cancer
development--in two of the trials it actually made things worse."
This cautionary tale, with it lessons of leaping before looking--and on the wrong bandwagon, no less -- resides firlmy in
the back of Nelson's mind. "It was quite stunning," he says, "there was a lot of egg on a lot of faces. There are probably
a number of reasons why the trials worked out the way they did, related to what the animal models really modeled,
and who used the substance -- whether people continued smoking, and how beta carotene affected their lungs. In any
event, it didn't work as well as everyone assumed that it must. Although all the other stuff they found was certainly
true: People who ate a lot of fruits and vegetables did do better than people who didn't. It just wasn't necessarily beta
carotene."
For Nelson, this case highlights the trouble of trying to pinpoint an element of the diet and determine whether it has
the power to prevent cancer. Nonetheless, he and colleagues at Hopkins are cautiously optimistic about several
promising looking nutrients, and downright enthusiastic about one of them: Selenium.
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What does the concerned man -- who reads about lycopenes and selenium and
vitamin E and green tea and soy, and wants to change his diet somehow
-- do to reduce his risk of prostate cancer?
-- eventually leads to prostate cancer.
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The Promise of Selenium
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This discovery, like so many in science, was sparked by serendipity: In a large study several years ago, people
who had been treated for skin cancer were given selenium supplements, in hopes of preventing the cancer from
coming back. During the course of the study, the researchers noticed that the patients getting selenium seemed to
develop fewer other cancers -- prostate, lung, colon than patients in the placebo group. This finding intrigued Nelson,
who began investigating selenium's role in prostate cancer. It also prompted Hopkins researchers to design their
own case-controlled study, using the valuable data base of the BLSA (Baltimore Longitudinal Study of Aging, a
study begun more than 40 years ago and involving about 1,500 men, who return every other year for physical
examinations and medical tests).
In this study, H. Ballentine Carter, M.D., professor of urology, Nelson, and former Hopkins urologist Jim Brooks,
M.D., studied 52 men with cancer and 96 "age-matched controls," men who did not develop cancer. Their findings
were exciting: for one thing, they discovered that in both of this groups -- men who developed prostate cancer, and
men who did not -- the level of selenium in the blood dropped over time. In other words, selenium apparently
decreases in everybody, with age. "I don't think that has ever been shown before," says Carter. "And while
selenium goes down with age, there's no other cancer that increases more rapidly with age than prostate cancer.
For all we know, selenium levels are playing a role in that." This investigation also confirmed what the skin cancer
study had suggested -- that selenium seems to protect against prostate cancer. In the Hopkins study, men with the
lowest levels of selenium were those most likely to develop prostate cancer and men with the highest levels of
selenium were almost 50 percent less likely to develop it.
How does it work? It turns out that selenium is an essential component of glutathione peroxidase, an enzyme like
glutathione-S transferase p that helps the body fight off potentially toxic substances. "There's pretty strong evidence
that, first of all, selenium supplementation did not make anyone worse," says Nelson, invoking the beta carotene
study, "and that it did seem to reduce the number of people who are diagnosed with prostate cancer."
Also important to Nelson is that selenium seems to make a difference in the body within just a few years. "So you
can take it later in life, and still potentially change the course of the disease, which I think is encouraging." Nelson is
one of several scientists involved in planning a large, nationwide trial of selenium supplementation, to begin in 2000.
Selenium is found normally in fruits and vegetables; the average American probably eats about 70 micrograms of it
a day. However, this can vary, depending on where we live -- and, more importantly, where the food we eat has been
grown -- because some soils are far richer in selenium than others. Both Nelson and Carter speculate that in the
future, when men go to the doctor for a PSA blood test, they will also have their selenium level checked. If it turns
out to be low, just taking a selenium supplement -- one 200-microgram pill (already available where most vitamins are
sold) may help ward off prostate cancer.
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"While
selenium goes down with age, there's no other cancer that increases
more rapidly with age than prostate cancer. For all we know, selenium
levels are playing a role in that."
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Other
Potential "Good Guys"
Of the many food-related elements being studied as potential "nutraceuticals," or dietary supplements, research on
selenium is furthest along, Nelson believes. But there are several promising candidates for study, including:
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Vitamin
E.: In the same upcoming selenium trial, vitamin
E will also be studied as another potential protector against
prostate cancer. (Although the specifics are still being worked
out, the men in the trial will probably be placed in one of
four groups: Men taking selenium alone; those taking viamin
E alone; those taking both selenium and vitamin E; and those
taking a placebo.) Oddly enough, says Nelson, some of the best
evidence that Vitamin E may help prevent prostate cancer came
from one of the infamous beta carotene trials, done in Finland.
(In this trial, men who smoked were given either supplements
of beta carotene alone, Vitamin E alone, both Vitamin E and
beta carotene, or placebo.) "The egg-on-the-face part was that
both beta carotene groups, whether or not they got Vitamin E,
did worse, and got more lung cancer," explains Nelson. "But
as they went back and analyzed this trial, they noticed that
there did seem to be less prostate cancer in both vitamin E
groups, Whether or not you got beta carotene, if you got Vitamin
E, you had less prostate cancer." Although the evidence in favor
of Vitamin E is not as strong as that supporting selenium, Nelson
believes it looks promising.
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Lycopene:
Lycopene has been tagged as a potential biomarker, but it's
already gotten a lot of advance publicity; "This idea is very
popular with a lot of patients," says Nelson. "The story here
actually started in a food frequency questionnaire," where the
common dietary theme in men who had less prostate cancer was
food with tomato sauce, like pizza or spaghetti. "This led scientists
to hypothesize that there might be something in tomatoes that
was affected by heat in such a way as to make it better absorbed."
But whether or not lycopene can prevent prostate cancer has
not yet been proven, cautions Nelson. There are several "next
steps" in this research that need to happen. "We need to know,
is there more lycopcne in the bloodstream of people who don't
have prostate cancer than those who do. Are there lower levels
among people who are going to get prostate cancer?" (This could
be tested in a study such as the BLSA, which has decades' worth
of data already stockpiled.) "And then the next level of evidence
is to give somebody this micronutrient, or administer it to
him in a controlled way, and see what the outcome is - either
it does or doesn't do what it's supposed to." One problem with
studying any potential preventive treatment in prostate cancer,
he notes, is that such outcomes can take years; therefore, it
might be good to look to see if his PSA falls."
One reason Nelson is interested in lycopene is simply that--unlike many substances, including some antibiotics-it
does manage to reach the prostate. "That's something that has worried me about a variety of candidate prevention
drugs and compounds," he says,. "because not everything you swallow ends up in your prostate."
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Green
tea.
"A significant percentage of people drink more tea than water,"
says Nelson. Some components of green and brown tea, including
catechin, EGCG (epigallo-catechin-gallate) and epicatechin are
being studied. "You hear stories about mystical, magical properties
of these components of green tea," Nelson says, "and in animal
studies and cell culture, they are biologically active molecules.
The big question remains: Is consumption of large amounts of
green tea the reason that people in Asia get less prostate cancer?
I don't think we know that directly Several clinical trials
of green tea components, and their effect on several forms of
cancer, are under way. "Is it harmful? Probably not. Will it
work? Obviously, the Chinese drink a lot, there is stuff in
there that's biologically active. Beyond that, it's anybody's
guess."
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Soy:
Soy contains cancer-fighting products called isoflavones, including
one called genistein "which has been purported to do all kinds
of things is actually present in high-enough concentrations
at the right time in the right place -- next to a cancer cell".
Soy is indeed a staple of the Asian diet, but even this is complicated:
"If you are deriving a lot of your protein nutrition from soy
products, that means you probably aren't deriving it from other
sources" -- such as red meat. Which brings us to the "sins of
omission and sins of commission" argument. Is soy good for us
because of some key ingredient? Or does it prevent cancer because
of all the things we're not eating instead? (For example, there
aren't many soy-bacon-cheese megaburgers in the Western diet.)
"We just don't know," says Nelson.
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Sulfuraphane
:Found in cruciferous vegetables, sulfuraphane seems
to protect against several cancers by turning up the body's
production of protective enzymes. But it's not yet clear, says
Nelson, whether prostate cancer is one of them.
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And
Finally, a Candidate "Bad Guy" -- Charred meat
is bad. We create carcinogens, or cancer-causing agents, with
every pork chop, steak or hamburger we grill or fry; one of
them is called PhIP "PhIP is a pro-carcinogen," explains Nelson.
"It's not chemically very reactive by itself; it needs to be
metabolized to something more dangerous." In the liver, PhIP
is transformed into a chemical called Nhydroxy PhIP For some
cells in the body-- including prostate and breast cells -- this
new chemical is far more dangerous, because it attacks DNA.
In laboratory animals, the PhIP carcinogen can even cause breast
cancer and prostate cancer. Working with scientists in the School
of Public Health -- Tom Kensler and John Groopman, and graduate
student Chad Nelson -- Nelson is interested in using PhIP as
a marker. PhIP causes telltale changes, or adducts, to the DNA--picture
barnacles on a sailboat--that can be monitored. "If we can induce
protection enzymes," with some dietary agent, "then we ought
to see less PhIP adducts in the DNA," says Nelson.
So what does the concerned man -- who reads about lycopenes and selenium and vitamin E and green tea and soy,
and wants to change his diet somehow -- do to reduce his risk of prostate cancer? "I'd have almost no reservations
about advising someone to make sure his selenium levels are not too low," says Nelson. Beyond that, eat plenty of
fruits and vegetables, and less red meat. And beyond that, take every story about a new dietary "wonder drug" with --
pardon the food imagery -- the proverbial grain of salt. It's just that we've been burned," says Nelson, "we've been
taken down the glory path. If there's skepticism, it's not because scientists hate alternative medicine, it's because
we want to be careful." In fact, he adds, underscoring all of this is "a great deal of enthusiasm driving a lot of
laboratory and clinical trial research, to get to the bottom of this. So, far from being skeptical, scientists are actually
trying to figure it out."
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