Affiliation of authors: Division of Oncology, Department of Medicine, Duke University Medical Center, Durham, NC
Correspondence to: Brooke Ratliff, MD, Division of Oncology, Department of Medicine, Duke University Medical Center, Box 3841, Durham, NC 27710 (e-mail: ratli006{at}mc.duke.edu)
The article by Stearns et al. (1) provides evidence that the tamoxifen metabolite endoxifen (4-hydroxy-N-desmethyltamoxifen) is equipotent with 4-hydroxytamoxifen in inhibiting estradiol-stimulated MCF7 cell proliferation. Further, they show that paroxetine can potentially interfere with metabolism of tamoxifen to endoxifen through an inhibition of CYP2D6. Stearns et al. (1) speculate that, as a result, coadministration of tamoxifen and paroxetine might decrease the therapeutic value of tamoxifen treatment. Because paroxetine has a valuable role in controlling hot flashes, a common side effect of tamoxifen treatment, the article by Stearns et al. (1) provides important information for the many women taking tamoxifen and taking or considering paroxetine or other selective serotonin reuptake inhibitors (SSRIs).
Tamoxifen is a selective estrogen receptor modulator used in the treatment of estrogen receptorpositive breast cancer in both metastatic and adjuvant settings. The breast cancer prevention trial showed that women who received tamoxifen had a 45% reduction in breast cancer occurrence (2). Although tamoxifen is an active agent against breast cancer, its exact mechanism(s) of action is still unknown. Tamoxifen appears to have both cytostatic and cytotoxic activity. The "classic" mechanism of estrogen and anti-estrogen action requires that the ligandreceptor complex binds to defined promoter elements and modulates transcription. This mechanism appears to have cytostatic effects (3). Tamoxifen has also been shown to be cytotoxic, initiating apoptosis in estrogen receptorpositive breast cancer cells and acutely damaged, estrogen receptorpoor normal human breast epithelial cells in vitro (4,5). We have recently shown that apoptosis induced by tamoxifen is independent of the classic pathway of tamoxifen action, involved plasma membranemediated regulation of AKT, mitochondrial depolarization, and caspase activation (5,6).
In the study by Stearns et al. (1), the serum concentrations of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen were approximately 155, 180, 1.1, and 12 ng/mL, respectively. The Kd of tamoxifen for the estrogen receptor is 4.5 nM, approximately the same as that for N-desmethyltamoxifen, whereas the Kd of 4-hydroxytamoxifen is 0.15 nM (6). With these values, estrogen binding to the estrogen receptor would be effectively blocked by tamoxifen or any of the noted metabolites. Therefore, a decrease in the concentration of endoxifen would not substantially affect estrogen receptor function. Given this information and the unknown role of endoxifen in treatment, we agree with Stearns et al. (1) that the use of paroxetine or other SSRIs should not be discontinued in patients receiving tamoxifen.
REFERENCES
1 Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst2003;95:175864.
2 Fisher B, Constantino JP, Wickerham CDL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst1998;90:137188.
3 Riggs BL, Hartmann LC. Drug therapy: selective estrogen-receptor modulatorsmechanism of action and application to clinical practice. N Engl J Med2003;348:61829.
4 Perry RR, Kang Y, Greaves B. Effects of tamoxifen on growth and apoptosis of estrogen-dependent and -independent human breast cancer cells. Ann Surg Oncol1995;2:23845.[Abstract]
5 Dietze EC, Caldwell E, Grupin SL, Mancini M, Seewaldt VL. Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53() normal human mammary epithelial cells by inducing mitochondrial depolarization. J Biol Chem2001;276:538494.
6 Dietze EC, Troch MM, Bean GR, Heffner JB, Bowie ML, Rosenberg P, et al. Tamoxifen and tamoxifen ethyl bromide induce apoptosis in acutely damaged mammary epithelial cells through modulation of AKT activity. Oncogene, in press.
7 Coezy E, Borgna JL, Rochefort H. Tamoxifen and metabolites in MCF7 cells: correlation between bonding to estrogen receptor and inhibition of cell growth. Cancer Res 1982;42:31723.
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