The widely used breast cancer drug tamoxifen (Nolvadex®), which can become less effective over time, might retain its full strength indefinitely if used along with a second drug, according to new research in mice conducted by investigators from the National Cancer Institute (NCI), part of the National Institutes of Health, and their partners. The results appear in the December 11, 2006, issue of Cancer Cell*.
Tamoxifen has been used successfully since the 1970s to treat certain types of breast cancer and to prevent them from recurring after surgery. Clinicians observed that tamoxifen treatment initially reduced the rate of recurrence by nearly 50 percent. Over time, however, patients develop resistance to the drug and tamoxifen loses its effectiveness as a cancer treatment.
"Tamoxifen has been extremely important in the management of breast cancer," said NCI Director John E. Niederhuber, M.D. "Being able to overcome resistance would be an important advance."
In the study, the research team, led by William Farrar, Ph.D., of NCI’s Center for Cancer Research at Frederick, Md., found that the effectiveness of tamoxifen in cell cultures and in mice can be fully restored by the use of a compound called disulfide benzamide, or DIBA. The investigators confirmed their study hypothesis about DIBA’s effect on tamoxifen resistance by using the compound in mice that were engineered to have tamoxifen-resistant tumors and saw that tumor growth was reduced by nearly 50 percent when DIBA was administered.
"Exposure to DIBA causes certain physical changes to occur between the estrogen receptor and the biological machinery that stimulates cell division. By coincidence, these changes also restore the estrogen receptor to a form that makes it vulnerable once again to tamoxifen," said Li Hua Wang, Ph.D., lead author of the study.
Some, but not all, breast cancer cells have specific receptors that bind estrogen molecules circulating in the bloodstream. When estrogen binds to the estrogen receptor, it triggers a series of events that promote cell division. If the cell is a breast cancer cell, this interaction leads to tumor growth. In women with estrogen receptor-positive cancers, cancer cell growth is strongly influenced by estrogen.
Tamoxifen works by binding to estrogen receptors in place of estrogen and blocking the signals that lead to cell division. Initially, tumor growth slows or stops altogether. With continued tamoxifen treatment, however, the estrogen receptor and the estrogen-dependent signaling pathways in the cell can become altered, rendering tamoxifen ineffective as an inhibitor. In some cases, tamoxifen begins to act like estrogen and can stimulate tumor growth.
DIBA and related compounds are being studied because of their ability to disrupt cellular activity at the genetic level. These so-called electrophilic compounds were first investigated for possible use against AIDS because they can block the human immunodeficiency virus (HIV) from replicating. The HIV studies are ongoing.
"This basic study generated exciting results in our mouse model and suggests a promising approach that might be tried in human patients," said Farrar. His laboratory is now exploring ways to produce DIBA in a form that is water soluble so it could be administered as a pill, the same as tamoxifen. If successful, this could set the stage for preclinical studies.
Collaborators on the research include Georgetown University, Washington, D.C., Baylor College of Medicine and The Methodist Hospital, Houston, Texas, and the National Institute of Allergy and Infectious Diseases, Bethesda, Md.
* Wang LH, Yang XY, Zhang X, An P, Kim H, Huang J, Clarke R, Osborne CK, Inman JK, Appella E, and Farrar WL. Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer. Cancer Cell, December 11, 2006; Vol. 10, Issue 6.
