Animal model research indicates breast cancers may remain sensitive to tamoxifen indefinitely if it is given with the compound disulfide benzamide, according to an article in the December 11 issue of Cancer Cell.

"Tamoxifen has been extremely important in the management of breast cancer," said National Cancer Institute Director John E. Niederhuber, MD. "Being able to overcome resistance would be an important advance."

In the study, a research team led by William Farrar, PhD, found that the effectiveness of tamoxifen in cell cultures and in mice can be fully restored with 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; they found 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, PhD, lead author of the study.

When tamoxifen treatment is given to patients with breast cancer, the estrogen receptor and estrogen-dependent signaling pathways can become altered so that tamoxifen becomes 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.