Tamoxifen as an Immunomodulating Agent
Part of the
Hans Selye Symposia on Neuroendocrinology and Stress
book series (HSSN, volume 3)
The nonsteroidal antiestrogenic agent, tamoxifen (TX), has gained wide therapeutic application for the treatment of breast carcinomas and of some other sex hormone dependent tumors.1 Numerous investigations indicate that TX is capable of combining with the estrogen receptor of tumor cells which results in partial activation of the receptor, but without the growth promoting effect of estradiol (E2), which is the proper ligand for the receptor. For this reason TX and related drugs (ethamoxytriphethol or MER25, and clomiphene) are referred to under the collective term, nonsteroidal antiestrogens. 2 However, it was also demonstrated that nonsteroidal antiestrogens are able to inhibit the stimulatory effect of growth factors, such as epidermal growth factor or insulin, on human breast carcinoma cells in the complete absence of estrogens. Moreover, a cytotoxic effect was also observed when the antiestrogens were used at 4 µM concentration or higher. The presence of the estrogen receptor was still necessary for these effects. Therefore, Rochefort 3suggested that these agents be named estrogen receptor targeted drugs, rather than antiestrogens. However, it is a well established clinical fact that TX is capable of inducing regression of tumors that lack the classical receptor for E2.4–6 False negative receptor assay results were proposed as one possibility for this observation. Another possibility is a favorable influence of TX on immune host defence mechanisms. The available evidence supporting this latter possibility is discussed below.
KeywordsMixed Lymphocyte Reaction Human Peripheral Blood Lymphocyte Cytotoxic Reaction Estrogen Receptor Negative Breast Cancer Nonsteroidal Antiestrogen
J.S. Patterson and L.A. Battersby, Tamoxifen: an overview of recent studies in the field of oncology, Cancer Treat. Rep.
L.J. Lerner and V. C. Jordan, Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture, Cancer Res.
H. Rochefort, Nonsteroidal antiestrogens are estrogen-receptor-targeted growh inhibitors that can act in the absence of estrogens, Hormone Res.
M. Baum, Novaldex Adjuvant Trial Organisation: Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer; analysis at six years, Lancet
E. Baral and F. Vanky, Effect of tamoxifen on the cell-mediated autotumor lysis, J. Clin. Lab. Immunol.
C.L. Vogel, D.R. East, W. Voigt and S. Thomsen, Response to tamoxifen in estrogen receptor-poor metastatic breast cancer, Cancer
1987; 60:1184(1987).CrossRefGoogle Scholar
E. Baral, H. Blomgren, S. Rotstein and L. Virving, Antiestrogen effects on human blood lymphocyte subpopulations in vitro, J. Clin. Lab. Immunol.
1985; 17:33(1985).Google Scholar
E. Baral, H. Blomgren, J. Wasserman, S. Rotstein and L. V. von Stedingk, Effect of tamoxifen on pokeweed mitogen stimulated immunoglobulin secretion in vitro, J. Clin. Lab. Immunol.
21:137 (1986).PubMedGoogle Scholar
T. Paavonen and L.C. Andersson, The estrogen antagonists, Tamoxifen and FC-1157a, display oestrogen like effects on human lymphocyte functions in vitro, Clin. Exp. Immunol.
D.J.T. Webster, G. Richardson, M. Baum, T. Priestman and L.E. Hughes, Effect of treatment on the immunological status of women with advanced breast cancer, Brit. J. Cancer
H. Joensuu, A. Toivanen and E. Nordman, Effect of tamoxifen on immune functions, Cancer Treat. Rep.
E. Nagy and I. Berczi, Immunomodulation by tamoxifen and pergolide, Immunopharmacology
E. Baral, S. Kwok and I. Berczi, Suppression of lymphocyte mitogenesis by tamoxifen, lmmunopharmacology
E. Baral, S. Kwok and I. Berczi, The influence of estradiol and tamoxifen on the mixed lymphocyte reaction in rats, Endocrinology
S. Rotstein, H. Blomgren, B. Petrini, J. Wasserman and L.V. Von Stedingk, Influence of adjuvant tamoxifen on blood lymphocytes, Breast Cancer Res. Treat.
J. Berry, B.J. Green and D.S. Matheson, Modulation of natural killer cell activity by tamoxifen in stage I post-menopausal breast cancer, Eur. J. Cancer Clin. Oncol.
R. Mandeville, S.S.Ghalli and J.-P. Chausseau, In vitro stimulation of human NK activity by an estrogen antagonist (tamoxifen), Eur. J. Cancer Clin. Oncol.
I. Screpanti, M.P. Felli, E. Toniato, D. Meco, S. Martinotti, L. Frati, A. Santoni and A. Gulino, Enhancement of natural killer-cell susceptibility of human breast-cancer cells by estradiol and v-Ha-ras oncogene, Int. J. Cancer
B. Kim, P. Warnaka and C. Konrad, Tamoxifen potentiates in vivo antitumor activity of interleukin-2, Surgery
L.J. Brandes, L.M. MacDonald and R.P. Bogdanovic, Evidence that the antiestrogen binding site is a histamine-like receptor, Biochem. Biophys. Res. Commun.
H. Maoz, N. Kaiser, M. Halimi, V. Barak, A. Haimovitz, D. Weinstein, A. Simon, S. Yagel, S. Biran and A.J. Treves, The effect of estradiol on human myelomonocytic cells. 1. Enhancement of colony formation, J. Reprod. Immunol.
A.M. Al-Sumidaie, The effect of tamoxifen and medroxyprogesterone on giant cell formation by monocytes from patients with breast cancer, J. Cancer Res. Clin. Oncol.
W. Troll and J.S. Lim, Tamoxifen suppresses tumor promoter-induced hydrogen peroxide in human neutrophils, Proc. Am. Assn. Cancer Res.
32:149(1991). (Abstract #891)Google Scholar
C.J.M. Stephens, F.T. Wojnarowska and J.D. Wilkinson, Autoimmune progesterone dermatitis responding to Tamoxifen, Brit. J. Dermatol.
I. Nemere and A.W. Norman AW, Steroid hormone actions at the plasma membrane: induced calcium uptake and exocytotic events, Mol. Cell. Endocrinol.
P. Sartor, P. Vacher, P. Mollard and B. Dufy, Tamoxifen reduces calcium currents in a clonal pituitary cell line, Endocrinology
D.A. Greenberg, C.L. Carpenter and R.O. Messing, Calcium channel antagonist properties of the antineoplastic antiestrogen tamoxifen in the PC12 neurosecretory cell line, Cancer Res.
47:70 (1987).PubMedGoogle Scholar
P.A. Henkart, Mechanism of lymphocyte mediated cytotoxicity, Ann. Rev. Immunol.
J.D.E. Young, Killing of target cells by lymphocytes: a mechanistic view, Physiol. Rev.
69:250 (1989).PubMedGoogle Scholar
L. Shi, R.P. Kraut, R. Aebersold and A.H. Greenberg, A natural killer cell granule protein that induces DNA fragmentation and apoptosis, J.Exp. Med.
A. Zychlinsky, L. M. Zheng, C.-C. Liu and J. D. Young, Cytotoxic lymphocytes induce both apoptosis and necrosis in target cells, J. Immunol.
R.P. Kraut, D. Bose, E.J. Cragol Jr. and A.H. Greenberg, The influence of calcium, sodium and the Na+
antiport on susceptibility to cytolysin/perforin-mediated cytolysis, J. Immunol.
J.H.M. Cohen, L. Danel, G. Cordier, S. Saez and J.P. Revillard, Sex steroid receptors and restriction of estrogen receptors to OKT8 positive cells, J. Immunol.
W.H. Stimson, Oestrogen and human T lymphocytes: presence of specific receptors in the T- suppressor/cytotoxic subset, Scand. J. Immunol.
© Springer Science+Business Media New York 1994