Jim, Here's the WSJ anti-estrogen story (last August):
8/2/95 Drug May Offer Alternative To Estrogen-Replacement Therapy
By Elyse Tanouye Staff Reporter of The Wall Street Journal In
their search for safer alternatives to estrogen-replacement
therapy, scientists have discovered intriguing new uses for an
old class of compounds: anti-estrogens. Initial tests suggest
that these experimental drugs may prevent -- in one pill -- four
of the most devastating diseases of older women: osteoporosis,
heart disease, breast cancer and, in some cases, uterine cancer.
"It's potentially very exciting," says Gregory Mundy, professor
of medicine at the University of Texas' health-science center in
San Antonio. Anti-estrogens, he says, "do all the good things
estrogen does without some of the problems." The potential
benefits of anti-estrogens lie in the fact that they mimic
estrogen in some organs, such as the liver and bones, while
blocking estrogen's cancer-promoting effects in other tissues,
such as the breast and uterus. Having shown promise in test
tubes and animals, anti-estrogens must still undergo extensive
testing in humans. But if they work as expected, they could
obviate the decision-making older women now face: whether to
take estrogen after menopause to protect their bones and heart,
as many doctors urge them to do, or to avoid the hormone because
it may also raise their risk of breast and uterine cancer.
Seeing a huge market potential for anti-estrogens,
pharmaceutical companies are racing to get their versions
through clinical trials. Eli Lilly & Co. appears in the lead
with its drug, raloxifene, which is in late-stage human testing
against osteoporosis. Pfizer Inc., SmithKline Beecham PLC,
Zeneca Group PLC, American Home Products Corp., and Ligand
Pharmaceuticals Inc. are also working on anti-estrogens.
Anti-estrogens got their name because scientists were initially
only aware of the drugs' ability to block estrogen's
cancer-promoting role in breast tissue. The anti-estrogen
tamoxifen, sold by Zeneca under the brand name Nolvadex, has
been used as a breast-cancer therapy in the U.S. since 1978 and
is currently being tested to see whether it can prevent breast
cancer. Some anti-estrogens were developed as alternatives to
tamoxifen but for various reasons sat around on drug-company
shelves for years. In the mid-1980s, scientists working
separately in the U.S. and in France made some important
breakthroughs in the understanding of how and where estrogen
works in the body by identifying the estrogen receptor inside
certain cells. Around the same time, medical researchers
observed that women taking tamoxifen lost less bone mass and had
lower cholesterol than women who weren't on the drug. They had
expected the opposite effect because anti-estrogens block
estrogen, which protects the bones and heart. Moreover, in the
uterus, scientists observed that tamoxifen also sometimes acts
like estrogen by stimulating cancer cells. Belying its name, the
anti-estrogen was acting like estrogen in some places. Over the
next few years, scientists learned that estrogen and
anti-estrogens compete with each other to attach to the estrogen
receptors that are found throughout the body. The estrogen
receptor changes its shape after estrogen or an anti-estrogen
binds to it, taking on one shape with estrogen, and other shapes
with the different anti-estrogens, according to Donald P.
McDonnell, associate professor of pharmacology at Duke
University Medical Center. The receptor's shape determines
which genes it can turn on. The activated genes produce proteins
that go on to regulate different processes in the body, such as
bone remodeling or cancer cell growth. When estrogen binds to
the receptor, it activates about 100 genes, says Robert B.
Stein, chief scientific officer of Ligand. Anti-estrogens
activate just some of those genes, he says, and the task of drug
researchers has been to find the compounds that activate the
beneficial genes. Estrogen can't bind to a receptor already
occupied by an anti-estrogen and can't start the complex
processes leading to cancer-cell growth, according to Peter
Kushner, assistant research biochemist at the University of
California, San Francisco. Researchers at Lilly began to take
note of the anti-estrogen developments in the mid-1980s and
developed a number of compounds, including raloxifene. The
company first tested the compounds against breast cancer but
shelved the testing to put resources in other projects, says
John D. Termine, head of Lilly's bone-research program. But a
handful of Lilly scientists continued to work with the drug.
When Dr. Termine came to Lilly from the National Institutes of
Health to set up the company's bone-research program in 1991,
the researchers urged him to take a look at the work they had
done on raloxifene. Impressed with what he saw, he immediately
began testing the drug against osteoporosis. "My boss said,
`This thing could be a high-tech hormone-replacement therapy,'"
he recalls. In early human clinical trials, raloxifene appeared
to be as effective as estrogen in reducing bone loss and
lowering cholesterol. The drug also appears to protect against,
rather than cause, uterine cancer, Dr. Termine says. The drug is
currently a year into a four-year clinical trial, but if interim
data after the second year are strong enough, Lilly may seek
marketing approval early, he says. Pfizer is working with two
anti-estrogen compounds, one licensed from a European company,
Klinge Pharma GmbH and the other from a research collaboration
with Ligand. The Klinge compound, droloxifene, is very similar
to tamoxifen, but without any apparent link to uterine cancer,
says Allen Kraska, Pfizer group director of clinical research.
The drug is in late-stage testing against breast cancer and in
preliminary human tests for osteoporosis. As scientists explore
anti-estrogens' potential benefits, they are wary about possible
side effects. Tamoxifen causes hot flashes and other menopausal
symptoms in some patients. And some tamoxifen patients have
complained about depression, Dr. Kushner says. Estrogen
receptors appear active in a wide range of tissues. For example,
estrogen appears to protect against Alzheimer's disease and to
reduce colon-cancer risk, according to researchers. The effects
of an anti-estrogen in those areas probably won't be fully
understood until years after the drug is on the market. "This
particular field is in its infancy," says Conrad Johnston,
professor of medicine at Indiana University School of Medicine.
"That you can design an estrogen-like compound that will work in
one place as an estrogen and as an antagonist someplace else is
new and exciting, and I think will lead to better drugs."
Anti-Estrogens in Development
COMPANY DRUG STATUS
Eli Lilly Raloxifene Late-stage testing (Phase
III) against osteoporosis
Pfizer Droloxifene Phase III testing against
breast cancer; intermediate stage testing
(Phase II) against osteoporosis
Unnamed Preclinical testing compound
from Ligand against osteoporosis Zeneca
Tamoxifen National Cancer Institute testing to prevent
breast cancer ICI182780
Preclinical development against breast cancer
SmithKline Idoxifene Phase II testing against
breast cancer; preclinical testing against
osteoporosis
American
Home Unnamed Exploratory
& Ligand compounds
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