An estrogen is any chemical compound with estrogenic (feminizing) effects. The estrogen produced in the human body is estradiol, a steroid hormone. Women, of course, need estradiol to lead healthy lives and bear children. Men need it, too: for example, men must convert testosterone to estradiol in order to build bone tissue.

On the down side, some cancers, such as some types of breast cancer, are fueled by estradiol; they're said to be estrogen-responsive. And the estrogens in birth control pills or hormone replacement therapy carry risks for some women.

The SIUC group may have found a way to dismantle this double-edged sword--to separate useful estrogenic effects from unwanted or harmful effects. Like so many scientific advances, this one was unplanned.

Cal Meyers, professor emeritus of chemistry and director of the Meyers Institute for Interdisciplinary Research in Organic and Medicinal Chemistry, picks up the story. "We were treating estradiol with carbon tetrachloride--just doing basic research on electron transfer during fundamental chemical-reaction studies," he says.

"When we did this we found that the ring structure [characteristic of steroids] opened up, so that the compound was no longer a steroid. We had the compound tested and found that it was very estrogenic."

By this simple chemical reaction, Meyers' lab had created a nonsteroidal, estrogen-like compound. Its name is such a mouthful--bisdehydrodoisynolic acid--that they simply call it BDDA. Meyers and several colleagues--chemist Yuqing Hou, reproductive physiologist Todd Winters, nutrition physiologist Bill Banz, molecular biologist Stuart Adler, and biochemist Walter Dandliker (all but the latter are with SIUC)--have patented the use of BDDA as a potential treatment for prostate cancer and other medical conditions.

Estradiol and other estrogenic compounds once were used to treat prostate cancer, because they shrink prostate tissue and blunt testosterone production. Unfortunately, they also shrink the testes, causing impotence and sterility; they have other feminizing side effects, such as breast enlargement; and they promote blood clots. But BDDA may change all that.

A plus for prostate cancer

BDDA, like many organic compounds, exists in two forms: a "right-handed" structure and a "left-handed" structure that are chemically identical mirror images of each other. They're referred to as the plus (+) and minus (-) structures, respectively. Meyers and Hou knew that these two forms of BDDA might have different effects on the body. So they convinced Winters, Banz, and veterinarian Nancy Henry--all with SIUC's Dept. of Animal Science, Food and Nutrition--to test them in lab animals.

Meyers initially patented BDDA as a weight loss agent, since the compound was found to promote weight loss in female mice rather than the weight gain associated with many estrogens. But Winters, Banz, and Henry also discovered another intriguing effect of BDDA. Testing it in normal male rats, they found that both forms of the compound shrank prostate tissue--but that the right-handed version, (+)-BDDA, did it with almost no shrinking of the testes or other feminizing side effects.

This finding raised the intriguing possibility that (+)-BDDA might be used to treat prostate enlargement or even prostate cancer. The team went on to determine that oral preparations of this compound, not just injected preparations, were effective--a key selling point for eventual studies in humans.

Working with cell cultures, Henry found that (+)-BDDA inhibits the growth of human prostate cancer cells. "The effect is statistically significant and consistent," she says.

At that point the team asked Dennis Lubahn, a physiologist at the University of Missouri, Columbia, to test (+)-BDDA on a special strain of transgenic mice that spontaneously develop prostate cancer. If the compound keeps the cancer in check in these animals, the SIUC team hopes that a pharmaceutical company will step in to fund stage-1 clinical trials in humans.

Designer drugs

The work with BDDA opens up the possibility of making other "designer" estrogens. Songwen Xie, a doctoral student working with Meyers, has developed "a battery of compounds that may be as good as or better than BDDA," Winters says.

Designer estrogens might be developed to treat some types of breast or uterine cancer, or to fine-tune birth control or hormone replacement therapy so these drugs have fewer undesirable side effects.

"It looks like the whole package [of estrogenic effects] is separable," says Stuart Adler, an associate professor of physiology who also is part of the team. "We may be able to pick and choose the effects we want."

Hormones like estradiol bind to proteins called receptors. In the case of estradiol, the receptors are located in the nucleus of the cell. After binding takes place, the hormone/receptor complex interacts with various proteins in the nucleus to change gene expression and produce hormonal effects.

"We used to think of this [binding] with receptors as being like a lock and key," says Adler. "If they were the right shape, compounds would fit into the receptor and open the lock. But we now know there are subtle shape differences among compounds that can activate the estrogen receptor."

As it turns out, the "lock" can be opened to varying degrees. Consequently, some compounds that fit the receptor rather poorly--that open it just partway--can still produce substantial estrogenic effects.

Just as surprising, some compounds produce estrogenic effects in some tissues and anti-estrogenic effects in other tissues. For example, the cancer drug Tamoxifen normally blocks estradiol's effects in the breast, but it acts like estradiol on the uterus. (Thus breast cancer patients on Tamoxifen must be closely monitored for uterine cancer.)

These selective effects gave rise to a new term: SERM, for selective estrogen receptor modulator. Tamoxifen was the first known SERM compound; Meyers and Adler think that BDDA may be another. BDDA "hardly binds at all" to the estradiol receptor, says Meyers--yet it has strong estrogenic effects. And like Tamoxifen, it produces only some of estradiol's effects.

This selectivity, which holds so much promise for medical applications, poses difficulties for cancer-related environmental research. Many industrial chemicals that are widespread in the environment can interact with estrogen receptors. Scientists want to know what potential health risks, including cancer risks, are posed by these so-called "environmental estrogens."

Because environmental estrogens may act as SERMs, toxicology testing of these compounds must be more comprehensive than scientists might have anticipated, Adler says. For example, you can't just look at effects in one type of tissue, because a SERM can be benign in some tissues but carcinogenic in others. Adler thinks that BDDA offers "a perfect model system" for exploring some of these complexities.

Oddly enough, phytoestrogens--estrogenic compounds produced by plants--may provide some defense against environmental estrogens. Winters, Banz, and Henry have studied the physiological effects of soy phytoestrogens (there are several different types of these compounds), including effects on reproductive tissue.

The promise of soy

Where cancer is concerned, they say, the soy story is promising, but complicated. Estrogenic soy compounds have different effects in different types of tissues and can actually make matters worse in the case of certain cancers. For example, some labs have found evidence that low doses of genistein, one of the soy phytoestrogens, can stimulate some types of breast cancer cells.

On the other hand, soy seems to have protective effects if consumed early on and regularly. People living in Asia, where high-soy diets are common, have much lower rates of prostate and breast cancer than U.S. residents do. By keeping some of the body's estrogen receptors occupied, soy phytoestrogens may be able to keep environmental estrogens from binding and having pernicious effects.

Henry notes that many animal studies indicate that soy offers protection against the risk of cancer from environmental estrogens. This protective effect isn't due solely to phytoestrogens, however; soy protein plays a role as well. Consumers should get their soy by eating foods like tofu, says Banz, not by taking supplements.

In a major three-year project, Winters, Banz, Henry, and Adler also are investigating the synergistic effects of soy phytoestrogens and certain vitamins on prostate cancer. The study is supported by a $429,148 grant through the Illinois Attorney General's Office from a vitamin antitrust settlement fund. "Other scientists have looked at phytoestrogens and vitamins separately," says Henry, "but putting them together is where we're getting great results."

The researchers fed one group of normal male rats a soy-free diet, a second group a low-phytoestrogen soy diet, and a third group a high-phytoestrogen soy diet. Within those three groups, some of the rats received a high dose of vitamin A, some received vitamin D, some received vitamin E, and some received no extra vitamins. After eight weeks, the team found that the diet combining vitamin E with a high level of soy phytoestrogens had a pronounced effect in shrinking the size of the prostate.

Henry then tested combinations of vitamins and various soy phytoestrogens on human prostate cancer cells. "Vitamins E and D in combination with each other and with soy phytoestrogens basically stop growth of prostate cancer cells [in culture]," she says. "We're excited about these results."

Of the phytoestrogens, genistein seems to have the most significant effects. The team now plans to implant human prostate cancer cells into immunosuppressed mice and see if the vitamin/soy combinations can hold the cancer cells in check or kill them.

Meanwhile, Adler is studying what happens when soy phytoestrogens bind to estrogen receptors. Scientists have found that two protein families in the nucleus act as modulators for estrogenic compounds. One family helps the compounds activate estrogen receptors; the other family has the opposite effect. These critical modulators vary across cell types, which may account for some of the selective effects SERMs have.

Adler has shown that at least one soy phytoestrogen, genistein, can change the levels of the modulators, making the cell less responsive to it and to other environmental estrogens. By doing so, genistein is telling the body, in effect, "We're not really estradiol, even though we look similar." This adaptation may prevent health problems by neutralizing what would otherwise amount to an increase in estrogen load.

With funding from the National Institutes of Health, Adler is investigating the molecular mechanisms and gene sequences that allow genistein and other SERMs to influence modulator levels. "If we can understand the different classes of modulators, we might be able to make cancer cells more responsive to therapy," he says.

Returning to the designer drug concept, he raises the possibility of tailoring cancer therapy by combining compounds that block certain effects with compounds that promote other effects.

"It's not just a pipe dream to think that we can do this," he says. "The goal is to go from the bench to the bedside. It's still a big step to get to clinical trials, but ultimately we want to be helping people."

Adds Meyers, "That's why interdisciplinary research is so important.

"We've got work to do."

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> Also see: On Target | Ginseng and Cancer: A Follow-up