© 1998 by Oxford University Press
"Within the next 2 years, it will be routine to prevent breast cancer in the postmenopausal population," predicted V. Craig Jordan, Ph.D., of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago.
Not long ago Jordan's statement -- made in New Orleans, at the American Association for Cancer Research in late March -- may have seemed a bit far-fetched. But the recent early release of the results from the tamoxifen prevention trial (see next page) makes Jordan's prediction more credible. The drug was successfully used to prevent breast cancer in high-risk women, ages 35 and up.
For Jordan, who did pioneering research in anti-estrogens, hearing the results from the tamoxifen trial was an emotional moment. "I just sort-of welled up," he said. "I've been totally committed to this for 30 years. . . . It's been a lifetime of struggle. I'm just thrilled."
Jordan's relationship with tamoxifen began in the 1960s when the drug was being tested in England as a morning-after pill. What worked in rats, however, did not carry over to humans. When preliminary studies in humans showed that tamoxifen failed to work as an anti-fertility drug, trials began testing its effectiveness against breast cancer.
With money from the Worcester Foundation for Experimental Biology in Shrewsbury, Mass., and advice from Elwood Jensen, who first isolated the estrogen receptor in 1958, Jordan successfully used tamoxifen in 1973 to prevent breast cancer in rats.
Jordan remembers when he did these initial animal studies. At that time, he was worried about possible side effects of the new drug -- that it might increase heart disease and reduce bone density. In fact, several clinical trials later, the opposite proved to be true. By the late-1980s, it was clear that tamoxifen could be used to treat estrogen receptor-positive breast cancer, to reduce contralateral breast cancer by 40%, and to lower the risks of heart disease and osteoporosis.
However, the increased risk of endometrial cancer first seen in animals in 1988 and later corroborated in postmenopausal patients, raised some concern about using tamoxifen in healthy women.
Gradually these findings led to a new paradigm in drug development, said Jordan; to design a drug that prevents osteoporosis and also may have certain beneficial side effects -- preventing breast and endometrial cancer. Enter raloxifene.
After 10 years of study, raloxifene was approved for the prevention of osteoporosis in January 1998, and preliminary clinical studies show the drug's breast and endometrial safety. More comprehensive breast and endometrial data from raloxifene trials will be presented at the American Society for Clinical Oncology meeting this month.
Jordan looks back on the past 30 years with amazement as so many things are beginning to come together. Besides the clinical data, scientists are beginning to understand on a molecular level how natural estrogens and the anti-estrogens tamoxifen and raloxifene bind to the estrogen receptor. Estrogen receptors, found in the nucleus of cells, become active when the hormone makes its way to the nucleus and binds to the receptor.
A report in last October's Nature described in detail how estradiol (the active form of estrogen) and raloxifene bind to the estrogen receptor. A protrusion in the structure of raloxifene binds to a particular amino acid (351) in the receptor and prevents a change in the folding of the receptor that normally occurs when estradiol binds. Previous experiments with a 351 mutant receptor corroborated this finding.
"If you imagine that the estrogen receptor looks like the open jaws of a crocodile, when the estrogen binds, the jaws close," said Jordan. "But the binding of raloxifene keeps the jaws from closing."
Understanding the molecular basis of the estrogens and anti-estrogens will help scientists unravel the roles that these compounds have on various parts of the body -- the breasts, uterus, brain, bones, and liver -- to regulate circulating levels of fat. These molecular data plus the results from human trials will help pharmacologists like Jordan discover simple laboratory tests that can identify which new drugs will be good bone-preserving agents and which will be good at preventing breast or uterine cancers, or heart disease.
Jordan's original goal of preventing four diseases (breast cancer, uterine cancer, coronary heart disease, and osteoporosis) with one pill may still be possible. "The anti-estrogens are now going through another evolution to become broadly available in general medicine as prevention maintenance therapies," he said.
Jordan stressed that we now know that both tamoxifen and raloxifene have anti-osteoporosis properties. And, compared to tamoxifen, raloxifene has shown improved uterine safety, although he admits that the uterine safety of raloxifene still needs further testing in larger clinical trials.
Furthermore, in light of the findings from the tamoxifen prevention trial, a large breast cancer prevention trial comparing tamoxifen to raloxifene in postmenopausal women (women considered high risk since 80% of breast cancers occur over the age of 50) could begin as early as fall. Jordan has been asked to be scientific chairman of the study.
And, finally, Eli Lilly and Co., Indianapolis, will begin recruiting 10,000 women at high risk for coronary heart disease this month to test the ability of raloxifene to prevent coronary heart disease. "So we'll know if raloxifene can have any impact on coronary heart disease in about 5 years. . . . That's when we'll have prevention maintenance therapy," predicted Jordan.
Jordan beams proudly as he thinks back, "These are truly the halcyon days of translational research."
-- Nancy J. Nelson
Anti-Estrogens Come of Age: A Pioneer Looks Back
A Molecular Window
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