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New Research Sheds Light On Why Women Build Resistance To Tamoxifen Breast Cancer Therapy (dateline July 30, 1999)

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 ( 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 ( 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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