How did a failed contraceptive become the first targeted therapy for the treatment of breast cancer? The transformation of tamoxifen, from cast-off to lifesaver, laid the foundation for a new class of therapeutics -- selective estrogen receptor modulators -- that could treat or prevent a variety of human diseases, including cancer and osteoporosis, according to V. Craig Jordan, OBE, Ph.D., D.Sc., a researcher at the Fox Chase Cancer Center in Philadelphia.
Jordan reports on efforts to use the lessons learned about tamoxifen to develop new hormone receptor-related drugs for both women and men at the 2008 Annual Meeting of the American Association for the Advancement of Science in Boston on February 15.
"As both a preventative and therapeutic agent, tamoxifen has been credited with saving the lives of more than a half million women over the last 30 years," says Jordan, the Alfred G. Knudson Jr., M.D., Ph.D., Chair in Cancer Research at Fox Chase. "The process of discovery that made tamoxifen a reality has given us insights into molecular mechanisms that are currently being used to advance the creation and refinement of better drugs."
In the 1970s, Jordan's laboratory pioneered the work that turned tamoxifen into a cancer therapy, which then jump-started a field of study into so-called designer estrogens. These drugs, called selective estrogen receptor modulators (SERMS), can have different effects on their targets, estrogen receptors, depending on where the receptor is located within a woman's body.
The SERM raloxifene, for example, exhibits an anti-estrogen activity that can prevent cancer in breast tissue, but in other tissue the same drug has an estrogen-like effect that increases bone density. Currently, raloxifene, which was also developed in Jordan's laboratory, is approved in post-menopausal women to prevent osteoporosis and treat breast cancer.
"The idea that SERMs could act like an estrogen in one place and an anti-estrogen in the other has created a new dimension in drug development," Jordan says. "Now we can look at the design of these drugs and see how they can be applied to modulate other receptor sites throughout the body."
According to Jordan, recent studies have shown light on the complex -- and seemingly contradictory -- mechanisms behind the activity of receptors for steroids, such as estrogen. These mechanisms include slight structural differences in the estrogen receptors themselves in different tissues, as well as co-regulatory molecules that can influence whether a SERM will turn on or shut down a particular receptor. Of the 48 or so members of the nuclear receptor family, which include the molecules inside cells that bind to estrogen and other hormones, nearly half are able to be regulated in some way.
"Our knowledge of how tamoxifen and raloxifene work is now being applied to develop new drugs that are selective male hormone receptor modulators that could be used in men to improve muscle weight during sickness, but without stimulating glands like the prostate," Jordan says. "Indeed, a whole variety of nuclear steroid hormone receptor mediated drugs are now possible because of the understanding of SERM action."
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