Dec. 3, 2003 The effects of tamoxifen, a therapy used in the treatment and prevention of breast cancer, may be limited by the use of a commonly prescribed drug to prevent side effects of the treatment, according to a study published in the Dec. 3 issue of the Journal of the National Cancer Institute.
"Our study suggests that tamoxifen's metabolism, and possibly its effectiveness, can be modified by the genetic makeup of the person taking the drug and by the use of another drug prescribed to reduce tamoxifen-related hot flashes," says the study's senior author David Flockhart, M.D., Ph.D., director of the Division of Clinical Pharmacology at the Indiana University School of Medicine. "Our conclusions indicate that more extensive research is appropriate."
Tamoxifen, a drug that modifies the effect of estrogen on cells, is widely and effectively used in many women as part of standard therapy for those with breast cancer and those at high risk of developing the disease. For about 80 percent of the women who take tamoxifen, hot flashes are a side effect of the therapy and 45 percent of those women rate them as severe.
Drugs commonly prescribed to remedy the problem are new antidepressants, paroxetine and fluoxetine, which are selective serotonin reuptake inhibitors (SSRIs). SSRIs have been shown to inhibit the enzyme that breaks down tamoxifen into chemical agents called metabolites, including 4-hydroxy-tamoxifen, which was believed to be tamoxifen's most active metabolite.
Twelve women with a history of breast cancer, but no current evidence of the disease, were enrolled in a yearlong clinical trial. The women had to have taken tamoxifen for four weeks prior to enrolling in the trial, and remained on the therapy until the trial's conclusion. Each woman also took paroxetine for four weeks.
Extensive laboratory analysis of the women's blood plasma showed a significant decrease in a metabolite of tamoxifen after treatment with paroxetine.
The researchers discovered a previously unknown metabolite which they named endoxifen. It was found to be present in substantially higher concentrations than 4-hydroxy-tamoxifen in women taking tamoxifen. It was clear that the concentration of endoxifen in the plasma was altered when paroxetine was used.
Endoxifen concentrations were reduced from 24 percent to 64 percent, with a mean decrease of 56 percent. The difference in the percentages of endoxifen concentrations corresponds to variations in the genetic composition of the women. Researchers hypothesize that this variation also may be the reason tamoxifen is more effective in some patients than others.
The research was supported by a grant from the National Institute of General Medical Sciences, part of the National Institutes of Health. First author of the article was Vered Stearns, M.D., assistant professor of oncology, Breast Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine.
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