Rockefeller and Michigan State Scientists Identify Dangers of Tamoxifen and Recommend Simple Corrective Measures
Researchers Urge Cautious Approach for Healthy Women Considering Tamoxifen
A team of researchers at The Rockefeller University and Michigan State University has identified a biochemical mechanism that may cause the potentially life-threatening side-effects associated with use of the anti-breast cancer drug tamoxifen, and has recommended steps to reduce the danger. The findings are reported in the June 25 issue of the Journal of Biological Chemistry.
“Understanding how tamoxifen works in cells allows us to screen for new drugs that retain the tumor-fighting abilities of tamoxifen without the negative side effects,” says lead investigator Sanford Simon, Ph.D., Walter Annenberg Research professor and head of the Laboratory of Cellular Biophysics at Rockefeller. “The pharmaceutical companies have made hundreds of drugs that resemble tamoxifen in their capacity to block estrogen binding to its receptor. However, testing all of these drugs in patients would involve considerable cost and time. Given the large number of women that are currently battling breast cancer, there is a great incentive to select drugs for clinical tests that are most likely to retain only the positive attributes of tamoxifen.”
Breast cancer afflicts one out of every eight women, and it is the most common form of cancer in women in the Western world. Most breast cancers depend on estrogen for their growth. Molecules on the surface of breast cancer cells, called estrogen receptors, bind to the hormone and respond to its growth-stimulating effects. Tamoxifen is also able to bind to these receptors, thereby blocking estrogen from binding and preventing the growth of new or recurring tumors. In a recent large scale study, tamoxifen also reduced the occurrence of breast cancer. Its ability to block tumor growth has proven so successful, that during this past year, it became the first drug approved by the Food and Drug Administration as a cancer preventative. During clinical studies, researchers also found that tamoxifen has a few additional advantages: it reduces the rate of osteoporosis and atherosclerotic heart disease, and it alleviates symptoms of menopause.
Unfortunately, tamoxifen also has demonstrated a number of serious side effects. Women who take tamoxifen have an increased risk of thrombosis (blood clots trapped in a blood vessel that block blood flow and prevent the delivery of oxygen and nutrients to a tissue), endometrial cancer, liver disease, and liver cancer. Understanding how tamoxifen works to cause all of these effects has been difficult. Some of the activities can be explained by its ability to mimic estrogen, but others cannot be explained so easily. Tamoxifen shares many its side-effects (e.g. on bone resorption and thrombosis) with raloxifene, another estrogen-receptor blocker.
Reporting in a recent issue of the Proceedings of the National Academy of Sciences, the researchers have shown that tamoxifen reduces the acidity of specific cellular compartments. In some circumstances, this may be beneficial and may account for the effects of tamoxifen on bone loss or the sensitivity of tumors to chemotherapeutics. However, such acidity in cellular compartments is important for many basic cellular functions. For example, proteins that are exported from the cell are processed in these acidified compartments. The cell requires this acid to activate many of these proteins. Further, the acid in these compartments helps to trap various environmental toxins away from the cytosol. Reducing the acid in these compartments may sensitize cells to these toxins thereby increasing the incidence of various cancers.
In their follow-up study, the researchers detail the mechanisms by which tamoxifen affects the cell. They show that tamoxifen accumulates into the membranes that both surround cells and separate the compartments of a cell. When tamoxifen is concentrated in these membranes it has two effects: It reduces any buildup of acid across the membrane and it modifies the electronic charges that are found on all membranes. Of greatest clinical significance is their demonstration that these actions of tamoxifen are independent of the cell’s estrogen receptor. Tamoxifen blocks the growth of breast tumors by interacting with the receptors for estrogen. Thus, the researchers have developed a way to select for those drugs that should inhibit the growth of breast tumors in the absence of the other effects of tamoxifen.
“Tamoxifen is an amazingly useful drug for controlling a wide variety of breast cancers,” says Dr. Simon. “Individuals with breast cancer should seriously consult with their physician concerning the appropriateness of the drug for them. However, until variants are found that do not have these side-effects, I would recommend a more cautious approach for any healthy woman who is considering treatment with tamoxifen to prevent the development of breast cancer.”
Simon’s co-authors on the paper are Yu Chen, B.S., at Rockefeller, and Melvin Schindler, Ph.D., at Michigan State University.
This research was supported in part by the National Cancer Institute, part of the federal government’s National Institutes of Health, by the American Cancer Society, and by the Wolfensohn, William and Helen Mazer, Pardee and Irving A. Hansen Memorial Foundations.