Breast cancer patients taking the drug tamoxifen (trade name
Novaldex) generally develop resistance to the drug two to five years
into treatment. A new study by scientists at Duke University Medical
Center and Novalon Pharmaceutical Corporation suggests there may be
a way to prevent tamoxifen resistance. The discovery could lead to
new drugs that either work better than tamoxifen or prevent a
woman's resistance to the drug.
Tamoxifen has been used to treat women with breast cancer for
more than 20 years and has been in clinical trials for about 30
years. In October 1998, tamoxifen became the first drug to be
approved for preventing breast cancer, after research showed it
reduced the chance of developing the breast cancer by 50% in women
with at high risk.
Tamoxifen is an "anti-estrogen" drug taken orally and works
by binding to estrogen receptors. Tamoxifen is a selective estrogen
receptor modulator (SERM). Anti-estrogens compete with estrogen to
bind to estrogen receptors. Tamoxifen has estrogen-like affects on
bone (it helps increase
bone density ), but tomoxifen is an
estrogen antagonists (anti-estrogens) that blocks or inhibit
estrogen affects in the breast and uterus. By blocking estrogen in
the breast, anti-estrogen agents such as Tamoxifen slow the growth
and reproduction of breast cancer cells.
About half of breast cancers have such estrogen receptors,
and tamoxifen treatments can be very successful at blocking
continued cancer growth. Over time, however, the tamoxifen stops
being effective as an anti-estrogen agent and begins to act on the
cell like estrogen itself.
According to a report in the July 30th issue of Science ( http://www.sciencemag.org) researchers now think they
know why this occurs. Apparently, the tamoxifen begins to change the
shape of the estrogen receptor, which forms an additional "pocket''
or surface that can bind to short proteins inside the cell called
peptides. The action of these peptides seems to change how the cell
perceives tamoxifen. Dr. Donald McDonnell, a Duke University Medical
Center pharmacologist, and scientists from the Novalon
Pharmaceutical Corporation (
http://www.novalon.com) in Durham lead the
research.
The finding sheds new light on the "unique'' mechanisms
underlying the development of tamoxifen resistance, McDonnell said.
Previously, he explained, researchers believed that tamoxifen
resistance developed as a result of the drug's estrogen mimicking
effects. "We now know from this how to develop drugs that can
possibly circumvent resistance,'' he said.
"The implications of our discovering this new pocket formed
by tamoxifen are quite exciting," added McDonnell. "What this means
is we can develop new drugs that target the estrogen receptor but
don't form this new pocket when they attach to it. On the other
hand, we can also develop a drug that will bind to this pocket and
block it, thereby preventing undesirable proteins from binding to it
while the woman is on tamoxifen."
The field of hormone replacement therapy is very important
since estrogen plays such a vital role in the health and well-being
of all women. The presence of estrogen exposure has been linked to
breast and uterine cancer, and estrogen deficiency has been linked
to osteoporosis, heart disease and cognitive
decline.
If researchers can discover a tamoxifen-like drug that does
not promote formation of the pocket, or a way to block the
additional binding site, they may be able to prevent tamoxifen
resistance.
The researchers at
Duke and Novalon are testing a new drug that shares some of the
properties of estrogen and tamoxifen but pose fewer risks and side
effects. Even if that new drug comes to the forefront, McDonnell
said tamoxifen would remain a front-line defense against breast
cancer because it is a "tried and true" treatment that doctors
throughout the US are accustomed to using. McDonnell said the next
step of the research to further test his new SERM to determine its
safety and efficacy in animals and humans.
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