This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mandlekar, S. Articles by Kong, A-N. T. Search for Related Content PubMed PubMed Citation Articles by Mandlekar, S. Articles by Kong, A-N. T.

Pharmacodynamics of Tamoxifen and Its 4-Hydroxy and N-Desmethyl Metabolites: Activation of Caspases and Induction of Apoptosis in Rat Mammary Tumors and in Human Breast Cancer Cell Lines¹

Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology [S. M., V. H., A-N. T. K.] College of Pharmacy and Department of Surgical Oncology, College of Medicine [K. C.], University of Illinois at Chicago, Chicago, Illinois 60612

The antiestrogen tamoxifen (TAM) is extensively metabolized by cytochrome P-450 in humans and rodents. The active, estrogen receptor-binding metabolites, 4-hydroxy TAM (OHT) and N-desmethyl TAM (DMT) have been well characterized. We showed that the s.c. injection of 1 mg/kg TAM in adult female Sprague Dawley rats bearing carcinogen-induced mammary tumors resulted in rapid serum decline of parent TAM but higher exposure of the metabolites, OHT and DMT. We found for the first time that the administration of TAM for a short time resulted in a delayed induction of caspase activity and apoptosis within the mammary tumors. When TAM, OHT, or DMT was added to human breast cancer cell lines in culture, each elicited a time- and dose-dependent induction of caspase activity, preceding apoptosis. Importantly, pretreatment of the cells with a pharmacological inhibitor of caspases [benzyloxy Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk)] blocked apoptosis induced by all three of the compounds, implicating a critical role of caspases in TAM-, OHT-, or DMT-induced apoptosis. The results obtained from these studies suggest that one possible mechanism of inhibition of mammary carcinogenesis and tumor growth in vivo may be the induction of caspase-dependent apoptosis, and that the metabolites OHT and DMT may contribute to the antitumor effect of TAM.

This article has been cited by other articles:

				J. Cheng, D. V. Yu, J.-H. Zhou, and D. J. Shapiro Tamoxifen Induction of CCAAT Enhancer-binding Protein {alpha} Is Required for Tamoxifen-induced Apoptosis J. Biol. Chem., October 19, 2007; 282(42): 30535 - 30543. [Abstract] [Full Text] [PDF]

				Y. M. Shah, M. Al-Dhaheri, Y. Dong, C. Ip, F. E. Jones, and B. G. Rowan Selenium disrupts estrogen receptor {alpha} signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells Mol. Cancer Ther., August 1, 2005; 4(8): 1239 - 1249. [Abstract] [Full Text] [PDF]

				S. F. Louis, B. J. Vermolen, Y. Garini, I. T. Young, A. Guffei, Z. Lichtensztejn, F. Kuttler, T. C. Y. Chuang, S. Moshir, V. Mougey, et al. c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus PNAS, July 5, 2005; 102(27): 9613 - 9618. [Abstract] [Full Text] [PDF]

				J. Gauduchon, F. Gouilleux, S. Maillard, V. Marsaud, J.-M. Renoir, and B. Sola 4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members Clin. Cancer Res., March 15, 2005; 11(6): 2345 - 2354. [Abstract] [Full Text] [PDF]

				K. B. Bouker, T. C. Skaar, D. R. Fernandez, K. A. O'Brien, R. B. Riggins, D. Cao, and R. Clarke Interferon Regulatory Factor-1 Mediates the Proapoptotic but Not Cell Cycle Arrest Effects of the Steroidal Antiestrogen ICI 182,780 (Faslodex, Fulvestrant) Cancer Res., June 1, 2004; 64(11): 4030 - 4039. [Abstract] [Full Text] [PDF]

				H. J. Thompson, Z. Zhu, and W. Jiang Identification of the Apoptosis Activation Cascade Induced in Mammary Carcinomas by Energy Restriction Cancer Res., February 15, 2004; 64(4): 1541 - 1545. [Abstract] [Full Text] [PDF]

				M. Cuendet, K. Christov, D. D. Lantvit, Y. Deng, S. Hedayat, L. Helson, J. D. McChesney, and J. M. Pezzuto Multiple Myeloma Regression Mediated by Bruceantin Clin. Cancer Res., February 1, 2004; 10(3): 1170 - 1179. [Abstract] [Full Text] [PDF]

				M. Obrero, D. V. Yu, and D. J. Shapiro Estrogen Receptor-dependent and Estrogen Receptor-independent Pathways for Tamoxifen and 4-Hydroxytamoxifen-induced Programmed Cell Death J. Biol. Chem., November 15, 2002; 277(47): 45695 - 45703. [Abstract] [Full Text] [PDF]