The Women's Health site also has older NY Times articles. Here's the one on Designer Estrogens. Donald McDonnell is a former LGND employee and current consultant. Bert O'Malley has been on LGND's Scientific Advisory Board since its inception. LGND has extensive programs and patents in these areas:
March 4, 1997
Drug Researchers Working To
Design Customized Estrogen
By JANE E. BRODY
When it comes to estrogens, Nature seems to have given
with one hand and taken with the other. In addition to
making women women, these hormones help to protect the
heart, bones and brain from the ravages of age. But they
also stimulate the breast and uterus, increasing the risk of
cancer in these tissues.
Now, however, researchers are hot on the trail of drugs that
offer many of the benefits of natural estrogens without the
serious risks that dissuade most women from taking
replacement hormones after menopause. Their eventual goal
is to produce a series of custom-designed compounds that
could be prescribed to meet each woman's particular needs.
The research has thus far found that estrogen exhibits an
extraordinary complexity and versatility that is at once
intellectually challenging and enormously promising to those
seeking practical solutions to some of the costliest and most
devastating effects of aging.
As one researcher, Dr. Donald P. McDonnell of Duke
University's department of pharmacology, put it, "With
current hormone replacement therapy, we're walking a
tightrope between positive and negative effects." While the
current therapy gives women a mixture of estrogens that stimulate every
estrogen-sensitive tissue in the body, for good and ill, he said, "we should be able to
customize compounds that have different effects in different tissues."
One such drug, raloxifene by Eli Lilly & Company, is already in the final stages of
clinical testing as an osteoporosis preventative that also protects the heart but does not
stimulate cell growth in the breast or uterus. It is among several estrogen-like
compounds in the pharmaceutical pipeline that can act selectively on estrogen-sensitive
tissues, although none is as far along the road to approval as raloxifene.
What made this development possible was the discovery that the various natural
estrogens and synthetic estrogen-like compounds do not all act in the same way and
that whether a cell is affected or not by a particular type of estrogen is not just a matter
of yes or no. Researchers have found that the cells' receptor for estrogen is not a
simple on-off switch with a static structure. Rather, the receptor turns out to be a
malleable molecule whose shape is dictated by the substances it hooks up with, much
like a water bed conforms to different bodies. The shape assumed by the estrogen
receptor when it binds with a given molecule determines its ability to turn on different
genes in the various body tissues that house these receptors. The ideal estrogenic
compound would foster the growth of bone cells, protect arteries from clots and fatty
sdeposits and preserve the vitality of the brain without triggering cell growth, and
perhaps cancer, in the breast and uterus.
"We are moving toward a wonder drug," Dr. McDonnell said in an interview. "We're
entering a new generation of hormone replacement therapy, and raloxifene will be the
first to arrive." Raloxifene is not quite as potent as natural estrogen in protecting the
bones and heart, and its potential to help maintain brain function has yet to be
assessed, but it appears to be free of serious side effects, said Dr. John D. Termine, a
biochemist at Eli Lilly who is overseeing the drug's development.
Critical to this practical research is a new understanding of how estrogens interact with
genes in the cell nucleus. Estrogen receptors, the molecular locks into which estrogen
keys fit, reside in the cell nucleus, acting like a telephone line between the caller,
estrogen, and the receiver, the genes. In the receptors' quiescent state, they are
covered by substances, called heat-shock proteins, that keep them in a state of
readiness to bind to estrogen. Once estrogen hooks up with the receptors, these
proteins drop off.
Until recently, Dr. McDonnell said, scientists assumed that the estrogen receptor was a
simple switch that was turned on by various estrogens. The switched-on receptor
could then activate genes by fitting into the nuclear proteins responsible for turning
genes in the DNA on and off -- the gene transcription apparatus. Such a
straightforward switch would act the same in every tissue.
But Dr. Benita Katzenellenbogen and her colleagues at the University of Illinois have
shown that different estrogenic compounds react with the receptor lock in different
ways, resulting ultimately in different effects on neighboring genes. Dr.
Katzenellenbogen, a professor of physiology and cell biology, has been studying
estrogens and the estrogen receptor for a quarter-century. In an interview, she
explained that the various estrogens and estrogen-like compounds -- the ligands -- fit
into the binding pocket of the estrogen receptor a little differently, changing the
conformation, or shape, of the receptor and producing an estrogen-receptor complex
with a particular shape. That shape, in turn, determines how the complex interacts with
the regulatory proteins and gene promoters needed to put the genetic machinery in
motion.
Dr. McDonnell said: "It is now apparent that different ligands -- hormones, drugs or
other compounds -- that bind to the receptor influence its overall structure and that
different cells have the ability to discriminate between different shapes of the receptor.
Thus, if the active end of the receptor assumed a square shape, it might fit into the
transcription apparatus in bone cells but have no effect on the transcription apparatus in
breast cells."
When these findings were first published, in the late 1980's, cell biologists immediately
recognized their significance for hormone pharmacology. But it took the advent of
tamoxifen, an estrogen-like drug that paradoxically blocks estrogen's action in the
breast, to convince pharmaceutical companies of their practical potential, said Dr. Bert
W. O'Malley, chairman of the cell biology department at Baylor College of Medicine in
Houston. Tamoxifen, marketed by Zeneca Pharmaceuticals, is currently being used to
prevent the recurrence of breast cancer, but it stimulates cell growth in other tissues. In
bone, for example, it fosters the production of the cells that form new bone,
osteoblasts, which is good, and in the uterus, it stimulates the growth of endometrial
scells, which is bad, because it can lead to uterine cancer.
Dr. O'Malley said the changing shape of the estrogen-receptor complex was not the
only factor that accounted for its diverse actions in estrogen-sensitive tissues. He
explained that certain proteins, called co-regulators, could make estrogen more or less
potent in a particular tissue.
Once the receptor complex becomes tethered to the transcription apparatus of the
gene, these co-regulator proteins -- both co-activators and co-repressors -- are drawn
to the site. If co-repressors dominate the mix, the receptor complex may be unable to
turn genes on or may have only a weak effect. If co-activators dominate, the genes are
turned on and dictate the production of new proteins.
"There's a little battle between these enhancing and inhibiting factors going on all the
time," Dr. O'Malley said. "The cell doesn't necessarily want genes to be turned on all
the time so it has both an accelerator and a brake, just like a car."
Dr. O'Malley and his colleagues have calculated that 90 percent of the potency of the
estrogen-receptor complex is determined by the particular combination of
co-activators and co-repressors recruited by the complex. They have shown, for
example, that tamoxifen's effects can be switched, changing it from an anti-estrogen to
an estrogen, simply by changing the levels of co-activators and co-repressors.
The relative amounts of co-activators and co-repressors in a given tissue can vary from
woman to woman, affecting each woman's sensitivity to the stimulatory effects of
estrogenic substances, Dr. O'Malley said. Thus, tamoxifen may protect the breast or
stimulate the growth of uterine cancer in one woman but not another.
"You can give 100 women the same amount of hormone," Dr. O'Malley said, "and the
dose will turn out to be too much for some women and not enough for others. In the
future, we should be able to measure the sensitivity to a particular hormone in a given
tissue and predict the ideal dose for each woman."
However, as the experience with tamoxifen has shown, a woman's sensitivity can
change with time, necessitating periodic monitoring of the effects of an estrogenic
substance on a given tissue. Although tamoxifen initially acts as an anti-estrogen in the
breast, blocking cell growth, breast cells in most patients begin to see tamoxifen as a
stimulant, not a repressor, after five or more years of use, Dr. McDonnell said. That
finding has prompted the National Cancer Institute to recommend that the drug be
used for only five years, not indefinitely.
However, Dr. McDonnell added: "Resistance to the benefits of tamoxifen does not
confer cross-resistance to other classes of estrogen. Therefore, it's likely that women
who fail on tamoxifen can go on a different class of estrogenic drug and resume the
preventive therapy."
A major challenge researchers face in looking for such drugs is that there is no
short-term indicator to show whether a particular estrogen-receptor complex has the
desired effect on breast tissue. For bone effects, substances in the blood can indicate
the rate of bone formation, and for heart effects, levels of cholesterol -- low-density
and high-density lipoprotein -- in the blood can be smeasured. But there is no direct
marker for activity in the breast. Nor is there a simple biochemical indicator to show if
a compound can get into the brain from the blood -- crossing the blood-brain barrier
-- to stimulate the brain cells involved in memory and learning.
"The study of estrogen compounds that might benefit the brain is just getting started,"
Dr. McDonnell said. "We first have to determine what compounds will cross the
blood-brain barrier and, if so, whether they will increase activity in the brain." |
