Tamoxifen derivative shrinks mouse tumors.

To treat breast cancer, which afflicts 1 in 10 U.S. women, physicians often use tamoxifen, a drug that blocks estrogen's stimulation of breast tumors.

In addition, scientists are evaluating tamoxifen as a potential protective agent for healthy women who have an elevated risk of breast cancer.

But tamoxifen produces side effects. It increases the risk of uterine and endometrial cancer, can cause hot flushes, and can disturb the central nervous system, triggering depression, irritability, and short-term memory loss.

To lessen these side effects and boost the drug's therapeutic powers, scientists have developed a tamoxifen derivative that is proving effective in fighting tumors in animals, says Marcus E. Brewster, a chemist at Pharmos Corp. in Alachua, Fla.

Speaking at last week's meeting of the American Chemical Society in Anaheim, Calif., Brewster described the design and synthesis of the new anticancer agent, tamoxifen methiodide. The compound dissolves more easily in water, he said, which impedes its ability to enter the brain's fatty tissues and disturb the central nervous system.

In collaboration with researchers at the Weizmann Institute of Science in Rehovot, Israel, Brewster and his colleagues are testing the tamoxifen derivative in rodents.

Results show that the new drug did not infiltrate the brains of rats. Cancerous tumors shrank in 90 percent of the mice tested and in 40 percent grew too small to measure Brewster reports.

"A chemical modification of the tamoxifen molecule designed to decrease its entry into the brain resulted in improved tissue selectivity," Brewster says.

As well as blocking estrogen stimulation of breast tumors without disturbing the nervous system, the new molecule has unexpected benefits--it strengthens bones without overstimulating the uterus.

This reaction occurs because, unlike tamoxifen, the new molecule does not fit well into the uterus' estrogen receptors, says Brewster. Therefore it does not upset uterine tissues and cause cancer.

On the other hand, Brewster and his collegues report, the tamoxifen derivative does fit well into the estrogen receptors of bones, stimulating growth and perhaps helping to prevent the onset of osteoporosis.

Women who take tamoxifen to prevent breast cancer should not have to suffer "hot flushes, depressions, and cognitive decline," Brewster says. "Breast cancer patients as well could benefit from a better quality of life if these side effects are prevented."

The new drug "appears to offer a breast cancer treatment and prevention alternative with the benefits, but without many of the limitations, of tamoxifen," he concludes.

Trials of tamoxifen methiodide in women may begin before the end of the year.