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

Can Prostate Cancer be Prevented?

William Nelson, M.D., Ph.D. (left) and James Brooks, M.D., Ph.D.

Consider the average American man at middle age, after a lifetime of the typical high-fat, low-fiber, vegetable- and fruit-poor "Western" diet. Throw in a genetic curve ball -- a family history of prostate cancer -- plus advancing age, which also increases risk. If he's ever going to develop prostate cancer, now is probably the time; he's ripe for it. In fact, it may already be percolating away inside him, as it is in so may American men -- more than 300,000 will be diagnosed with prostate cancer this year alone.

Now, say that man is Asian, and he's spent his life there, perhaps in mainland China. His risk of developing prostate cancer is the lowest in the world. Unless, of course, he chooses to emigrate to this country -- in which case, over time, his cancer risk will rise to the level of an American man's.

Clearly, although no one knows all the factors involved in developing prostate cancer, environment -- and this mostly means diet -- is terribly important. Why is this? What do Asians do right -- and what do Americans do wrong? Is the Western diet guilty of sins ofcommission -- too many french fries and hamburgers -- or omission -- not enough broccoli and carrots? And more importantly: If the Asian diet does, indeed -- as many scientists suspect -- contain cancer-thwarting agents, is it possible to figure out what those are and use them here -- to shore up the body's defenses and perhaps even ward off prostate cancer before it begins?

Oncologist William G. Nelson, M.D., Ph.D., and urologist James D. Brooks, M.D., think that one day, if they can find the right dietary agent, it will be possible to prevent prostate cancer. The key, they believe, lies in bolstering a crucial enzyme that's knocked out early in a man's journey toward prostate cancer.

In the genetic battle that happens years or even decades before prostate cancer even becomes detectable, glutathione-S transferase p -- a scavenger enzyme whose job it is to protect cells by disarming their enemies -- is one of the first casualties. Like Barney Fife, it is a well-meaning but vulnerable hero with a limited arsenal -- as Fife had only one bullet, this enzyme's weakness seems to be the switch that controls it. Unable to withstand the tide of cancerous genetic changes, this switch fails startlingly early (a discovery made by graduate student Wen-Hsiang Lee, Nelson, and Brooks in 1994.)

"This enzyme protects normal cells against bad things," says Brooks, "including things that damage the DNA and cause cancer. It gets turned off very early in the genesis of prostate cancer. It looks like this occurs in PIN" (PIN is prostate intraepithelial neoplasia, "funny- looking" cells that are strongly linked to prostate cancer and considered by some to be precancerous) -- even though the enzyme is present in normal prostate cells sitting right beside the abnormal ones. "It also looks like this happens in patients who have familial prostate cancer. So this is a change that's germane to prostate cancer: The enzyme has been gone from every single prostate cancer cell we've looked at -- which is the most common genetic change anyone has found yet."

Normally, the enzyme, found in every cell in the body, works by sopping up hazardous materials and neutralizing them -- toxic cleanup, on a cellular level. "It's just a teeny, weeny thing," says Brooks, "a little protein that will take toxins, in whatever form they may be, and inactivate them by hooking another chemical onto them. That chemical is glutathione" -- thus the "transferase" part of the enzyme's name. (Actually, the body's toxin-fighting arsenal includes a host of enzymes, and several different glutathione transferases).

So, how to strengthen glutathione-S transferase pi and its toxin-fighting comrades, so they can stand up to cancer? Nelson and Brooks believe the best "drug" for this may be some dietary agent that's been there all along -- if they can just figure out what that is. They have some good candidates, and they're narrowing their choices for clinical trials that they hope to begin soon. Here's how they got to this point:

How the work began: The search for adjuvant therapy:

In some forms of cancer, a mainstay of treatment is adjuvant therapy, a tough regiment of chemotherapy -- usually, high powered drugs that have shown some success at fighting cancer that's far more advanced -- given at the time of surgery in an effort to keep the tumor from coming back. "The hope is to kill cancer cells that have spread throughout the body, even though you can't see them," says Nelson. Usually, he adds, "when cancer comes back after the initial treatment -- and this is certainly true for prostate cancer -- it's not a failure of the surgical or radiation therapy. It's because the man had small, undetectable deposits of metastatic cancer before he ever shook hands with the surgeon."

There is no good adjuvant treatment for prostate cancer -- no all-powerful drug able to kill these lethal micrometastases while they're still tiny, still invisible. So, several years ago Nelson began looking for one. He was intrigued by a drug called melphalan, which used to be given at the time of surgery for breast cancer. Although, because of it's side effects, it has since been dropped in favor of better drugs, "it was effective, and it did improve the outcome of women undergoing surgery," he says. "The thing that struck me is, if you look at the behavior of melphalan when it's given to women with very advanced breast cancer, it's actually an extremely poor drug. It was not a good advanced treatment, yet it was a good adjuvant treatment."

Could this be because early and advanced cancer -- like the Mississippi as a trickle in Minnesota, versus the raging river that roars past New Orleans -- are two distinct things? "Early cancer may be a different beast entirely," says Nelson. "Or, at least, the way you cure it may be different." So, in a feat of scientific detective work, he began delineating the cell changes they found in early-stage, curable tumors (removed by surgeon Patrick C. Walsh, M.D., during radical prostatectomy) and in late-stage, metastatic disease. One change they noticed was that, as cancer advances, it often develops a "clever and nasty" chemical pump, called p-glycoprotein, which can expel certain cancer-fighting drugs from its cells almost immediately.

"But the cancer cells might not be so clever early on," Nelson notes. Maybe, they thought, if a drug could somehow beat the clock -- and get into the cells before this ejector button develops, it might have a better chance of working. Their search for other "bad" defense mechanisms led them to glutathione-S-transferase pi. Researchers at the National Cancer Institute had discovered the enzyme, and tracked its reactions in cancer cells exposed to low doses of a chemotherapeutic drug; gradually, the cancer cells were exposed to higher levels of the drug until they became completely immune to them. "They were totally resistant," Nelson says. "They could grow even though the drug was around. What those cancer cells did was two things: First, they made a lot of p-glycoprotein, so they pumped the drug out. The other thing they did was, all of a sudden, they made a lot of glutathione-S transferase pi." Was this enzyme a cause of drug resistance? In breast cancer, scientists had learned that when a woman's tumor makes a lot of glutathione-S transferase pi, adjuvant chemotherapy isn't nearly as effective as in women whose tumors make less of it.

"We decided to check it out, and we found that prostate cancers basically never make it," Nelson says. "The reason this is curious is that most cancers make a ton of it at the earliest stages." When a rat develops liver cancer, "the first thing that happens is that liver cells crank up this enzyme as high as they can. Some people think this is the last-ditch defense -- that the last thing the cell did before it became a cancer was to turn up this enzyme. If the cells become cancerous, most of them still have this enzyme cranked up."

Except in prostate cancer. "So then we thought," Nelson continues, "Is it possible that one of the reasons you get prostate cancer bay be that you can't turn up this enzyme?" Normal prostate cells make glutathione-S transferase pi. So why not prostate cancer cells? "They can't, says Nelson, "because the cancer basically killed the gene, inactivated it so it can't be turned on." If cancer is a series of steps -- or, as Nelson puts it, "genome mistakes, where genes are inactivated and other genes are mutated," this step, eliminating glutathione-S transferase pi, is apparently one of the first -- creating a more hospitable environment for cancer by knocking out one of the bouncers at the door. "You might imagine that a normal prostate cell, if it lost this enzyme, all of a sudden it's vulnerable," says Brooks. "Without this means of protecting itself, now it's susceptible to some carcinogen; it can't detoxify it anymore."

Where diet comes in

So: If a crucial enzyme can be eliminated, can the process work in reverse -- can it be built up, instead?

More than 30 years ago, scientists found that they could stimulate cancer-fighting enzymes in animals by giving them very low doses of carcinogens (cancer-causing agents). "It kind of makes sense," says Brooks. "Here's a toxin that's going in the body at very low doses, and the body's responding to it the way it usually handles toxins -- whether it be from a carcinogen or some charred food, something bad that you eat, the body responds to it by turning on these enzymes."

Recently, Hopkins scientist Paul Talaly, M.D., found that ordinary foods (particularly, broccoli) could also stimulate some cancer-fighting enzymes -- so much so, in fact, that cancer could actually be prevented in animals. For Nelson and Brooks, the puzzle of glutathione-S transferase pi suddenly began making sense: "What that made us wonder," says Nelson, "is, maybe this enzyme was really the critical player all along -- and if we'd had a lifetime of keeping it cranked up, maybe we wouldn't have eliminated it so easily."

Brooks has spent the last two years laboriously seeking dietary compounds that are prostate-specific -- that only stimulate enzymes in the prostate (so they won't be metabolized elsewhere before they ever reach the prostate). The goal is to find a substance that could be taken every day -- like quinine, years ago, to ward off malaria -- as prostate cancer prevention. "You turn on the enzymes by giving the dose over and over again," says Brooks. "And besides, if you think about cancer in general, it's probably a product of long-term exposure to bad things. A number of cancers occur late in life -- so it's probably the accumulation of a number of genetic 'hits' over a lifetime; it's probably a long-term exposure to badness. So if you're thinking about upregulating these enzymes, you probably have to do it over the long term."

The idea has much to recommend it, says Nelson. "If there is something, for instance, in the Asian diet that protects against life-threatening prostate cancer development indirectly, whatever it is that they're eating would be the world's greatest drug: Clearly, they must be able to take it for a lifetime, and without tremendous side effects."

Another bonus is that, traditionally, Americans do a better job of adding to their diet than taking away, Nelson says. "I'm worried that. as a giant public health strategy, if we were to say the problem is eating too many Big Macs, whether that would ever be a truly useful think to know. We already know that smoking cigarettes isn't good for you, and it hasn't helped that much. I think's it's going to be hard to change us into a vegetable-crunching society. But if I could tell you that eating soybean curd twice a week, or something like that, would keep you from ever getting prostate cancer, I believe people would do it. So I just like the idea of trying to figure out whether there's something in the Asian diet that's protective, because I think it'll be easy to supplement our diet as a preventive maneuver."

Would a man need to take this dietary supplement forever, or just during a crucial decade or two -- so the early stages of prostate cancer would develop when a man was in his eighties, instead of his sixties? Also, when should a man start taking it? High School? In his thirties? These and a host of other questions remain to be answered. Nelson and Brooks may begin the first limited tests of a dietary supplement -- once they have one selected -- within a few months.


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