Abstract
The antiproliferative action of the antiestrogen toremifene and recombinant human interferon-α2a (IFN-α2a) were examined on human breast cancer cell lines grown in culture and in the athymic mouse.
Solid tumors grew from an inoculation of a 99:1 ratio of hormone dependent (MCF-7) and hormone independent (MDA-MB-231) breast cancer cells without estrogen administration. However, estradiol supplementation significantly increased the rate of tumor growth. The daily administration of 1.35 × 106 U of recombinant human IFN-α2a resulted in a marked reduction of tumor growth in both estradiol-treated and non-treated mice. Toremifene administration (130 µg/day from a sustained release preparation) markedly inhibited estradiol stimulation of mouse uterine weight and partially reduced estradiol-stimulated tumor growth. The combination of IFN-α2a (1.35 × 106 u/day) with toremifene (130 µg/day) reduced estradiol-stimulated growth much below that of toremifene alone but not below that seen with interferon alone.
Toremifene (10−10-10−6M) did not inhibit the growth of hormone-independent MDA-MB-231 breast cancer cellsin vitro whereas it did inhibit the growth of hormone-dependent MCF-7 cells in phenol red containing media. IFN-α2a (1–10,000 u) inhibited the growth of both MCF-7 and MDA-MB-231 cells in culture; however, MCF-7 cells were approximately 10-fold more sensitive to interferon inhibition. This was consistent with the MCF-7 cells showing a greater sensitivity to interferon than MDA-MB-231 cells in the induction of 2′5′-oligoadenylate synthetase.
The heterogeneous tumor model in the athymic mouse suggests that differential sensitivities of breast cancer cells to the antiproliferative actions of interferon may influence the effectiveness of combination therapies.
References
Furr BJA, Jordan VC: Pharmacology and clinical use of tamoxifen. Pharmacol Ther 25: 127–203, 1984
King WJ, DeSombre ER, Jensen EV, Greene GL: Comparison of immunocytochemical and steroid-binding assays for estrogen receptor in human breast tumors. Cancer Res 45: 293–304, 1985
Shimada A, Kimura S, Abe K, Nagasaki K, Adachi I, Yamaguchi K, Suzuki M, Nakajima T, Miller LS: Immunocytochemical staining of estrogen receptor in paraffin sections of human breast cancer by use of monoclonal antibody: comparison with that in frozen sections. Proc Natl Acad Sci USA 82: 4803–4807, 1985
Perrot-Applanat M, Groyer-Picard M-T, Lorenzo F, Jolivet A, Hai MTV, Pallud C, Spyratos F, Milgrom E: Immunocytochemical study with monoclonal antibodies to progesterone receptor in human breast tumors. Cancer Res 47: 2652–2661, 1987
Van Netten JP, Algard FT, Coy P, Carlyle SJ, Brigden ML, Thornton KR, Peter S, Fraser T, To MP: Heterogeneous estrogen receptor levels detected via multiple microsamples from individual breast cancers. Cancer 56: 2019–2024, 1985
Robinson SP, Jordan VC: Antiestrogenic actions of toremifene in hormone-dependent, independent and heterogeneous breast tumor growth in the athymic mouse. Cancer Res 48: 1758–1762, 1989
Taylor-Papadimitriou J, Shearer M, Balkwill FR, Fantes KH: Effects of HuIFN-α2 and HuIFN-α (Namalwa) on breast cancer cell growth in culture and as xenografts in the nude mouse. J Interferon Res 2: 479–491, 1982
Balkwill FR, Goldstein L, Stebbing N: Differential action of six human interferons against two human carcinomas growing in nude mice. Int J Cancer 35: 613–617, 1985
van den Berg HW, Leahey WJ, Lynch M, Clarke R, Nelson J: Recombinant human interferon alpha increases oestrogen receptor expression in human breast cancer cells (ZR-75-1) and sensitises them to the antiproliferative effect of tamoxifen. Br J Cancer 55: 255–257, 1987
Gutterman JV, Blumenschien AR, Alexanian R, Yap HY, Buzdar AU, Cabanillas F, Hortobagyi GN, Hersh EM, Rasmussen SL, Harmon M, Kramer M, Pestka S: Leukocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma and malignant lymphoma. Ann Intern Med 93: 399–406, 1980
Borden EC, Holland JF, Dao TL, Gutterman JU, Wiener L, Chang YC, Patel J: Leukocyte-derived interferon (α) in human breast carcinoma. The American Cancer Society phase II trial. Ann Intern Med 97: 1–6, 1982
Goldstein D, Lazlo J: Interferon therapy in cancer: from imaginon to interferon. Cancer Res 46: 4315–4329, 1986
Berthois J, Katzenellenbogen JA, Katzenellenbogen BS: Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci USA 83: 2496–2500, 1986
LaBarca C, Paigen K: A simple, rapid, and sensitive DNA assay procedure. Analyt Biochem 102: 344–352, 1980
Merritt JA, Borden EC, Ball LA: Measurement of 2′5′-oligoadenylate synthetase in patients receiving interferonalpha. J Interferon Res 5: 191–198, 1985
Grossberg SE, Taylor JL, Sieberlist RE, Jameson P: Biological and immunological assays of human interferons. In: Rocklin R (ed) Manual of Clinical Immunology, 3rd ed. ASM Publishing, Washington DC, 1986, pp 295–299
Kimoto Y, Fujita M, Tagucha T: Interferon treatment of human stomach and breast carcinoma xenografts in nude mice. J Interferon Res 7: 345–356, 1987
Gutterman JN, Fine S, Quesada J, Horning S, Levine JF, Alexanian R, Bernhardt L, Kramer M, Spiegel H, Colburn W, Trown P, Merigan T, Dziewanowski Z: Recombinant leukocyte A interferon: Pharmacokinetics, single dose tolerance and biologic effects in cancer patients. Ann Int Med 96: 549–556, 1982
Kangas L, Nieminen A-C, Cantell K: Additive and synergistic effects of a novel antiestrogen, toremifene (Fc-1157a) and human interferons on estrogen responsive MCF-7 cellsin vitro. Medical Biology 63: 187–190, 1985
Goldstein D, Bushymeyer M, Witt PL, Jordan VC, Borden EC: Effects of type I and II interferons on cultured human breast cells: interaction with estrogen receptors and with tamoxifen. Cancer Res 49: 2698–2702, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Robinson, S.P., Goldstein, D., Witt, P.L. et al. Inhibition of hormone-dependent and independent breast cancer cell growthin vivo andin vitro with the antiestrogen toremifene and recombinant human interferon-α2. Breast Cancer Res Tr 15, 95–101 (1990). https://doi.org/10.1007/BF01810781
Issue Date:
DOI: https://doi.org/10.1007/BF01810781