This Article 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 Benz, C. Articles by Dannies, P. Search for Related Content PubMed PubMed Citation Articles by Benz, C. Articles by Dannies, P.

Tamoxifen and 5-Fluorouracil in Breast Cancer: Cytotoxic Synergism in Vitro¹

Departments of Medicine [C. B., E. C., J. G., T. W.], Obstetrics and Gynecology [A. E.], and Pharmacology [E. C., J. A., P. D.], Yale University School of Medicine, New Haven, Connecticut 06510

The cytokinetic and cytotoxic interactions involved in combining tamoxifen, methotrexate, and 5-fluorouracil were studied in two hormone-dependent human breast cancer cell lines, 47-DN and MCF-7. These cells had measurable cytosol and nuclear estrogen receptor and cytosol progesterone receptor. Growth of the MCF-7 cells in medium containing gelding serum was stimulated maximally by addition of 10 pM estradiol. Both MCF-7 and 47-DN cells showed dose-dependent in vitro growth inhibition on exposure to tamoxifen, and toxicity from tamoxifen at concentrations up to 10 µM could be prevented by 1 nM estradiol. After exposure of 47-DN cells to 10 µM tamoxifen, cytosol progesterone and nuclear estrogen receptor levels were still detectable at 30 and 60% of control values. With this same concentration of tamoxifen, 47-DN cells in S phase declined 50% in association with a buildup of G_0–1 cells. By clonogenic assay, tamoxifen enhanced 47-DN and MCF-7 cytotoxicity to 5-fluorouracil and 5-fluorouridine, but not to methotrexate alone. When given either concurrently or using a pretreatment-synchronizing schedule, tamoxifen enhanced markedly the growth inhibition of sequentially combined methotrexate and 5-fluorouracil. Isobologram analysis was used to prove that the cytotoxic interaction between tamoxifen and 5-fluorouracil was synergistic.

¹ Supported by Grants CH-145 and CH-235 from the American Cancer Society and Grants CA-08341, CA-27130, and CA-36773 from the National Cancer Institute. Also supported in part by a Pharmaceutical Manufacturers' Association Foundation research starter grant and a Swebelius cancer research award from Yale Comprehensive Cancer Center.

² To whom requests for reprints should be addressed.

³ Present address: Cancer Research Institute, the University of California at San Francisco, Parnassus Avenue, San Francisco, Calif. 94143.

⁴ Recipient of a faculty cancer research award from the American Cancer Society.

⁵ Some of this work performed as a requirement toward a doctoral of medicine degree.

Received 12/ 1/82. Accepted 8/ 4/83.

This article has been cited by other articles:

				C. Pico, M. Martin, C. Jara, A. Barnadas, A. Pelegri, A. Balil, C. Camps, A. Frau, A. Rodriguez-Lescure, J. M. Lopez-Vega, et al. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study Ann. Onc., January 1, 2004; 15(1): 79 - 87. [Abstract] [Full Text] [PDF]

				Y. Tan, X. Sun, M. Xu, X. Tan, A. Sasson, B. Rashidi, Q. Han, X. Tan, X. Wang, Z. An, et al. Efficacy of Recombinant Methioninase in Combination with Cisplatin on Human Colon Tumors in Nude Mice Clin. Cancer Res., August 1, 1999; 5(8): 2157 - 2163. [Abstract] [Full Text] [PDF]

				A. Shapira, E. Virolainen, J. J. Jameson, S. J. Ossakow, and T. E. Carey Growth Inhibition of Laryngeal UM-SCC Cell Lines by Tamoxifen: Comparison With Effects on the MCF-7 Breast Cancer Cell Line Arch Otolaryngol Head Neck Surg, November 1, 1986; 112(11): 1151 - 1158. [Abstract] [PDF]