A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions




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.

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.

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.

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.

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.

The Promise of Selenium

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.

"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." 

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:

  • 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.

  • 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."

  • 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."

  • 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.

  • 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.

  • 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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