Abstract
It has been reported that treatment with cimetidine, a histamine H2-receptor antagonist, increased survival and decreased the number of lung metastases in mice bearing the Lewis Lung carcinoma [29]. It was suggested that this effect was due to the ability of cimetidine to block histamine activation of suppressor lymphocytes and hence allow host defence mechanisms to inhibit tumour growth. In the present studies, C3H/He mice were implanted with a C3H mouse mammary adenocarcinoma on Day 0. This tumour metastasizes to the lungs in 30–50 days. Primary tumours were ablated with X-rays when they had grown to about 0·2g and animals were given drinking water with or without cimetidine (10 mg ml−1) until the end of the experiment. Cimetidine reduced the number of mice dying from metastatic disease from 7/15 (controls) to 3/13. Cimetidine treatment also prolonged survival of mice that did succumb to metastatic disease by about 12 days. The response of spleen lymphocytes to the mitogens phytohaemagglutinin and lipopolysaccharide was assessed in vitro by uptake of 3H-thymidine 0, 16, 45 and 58 days after tumour implantation. Lymphocyte responsiveness was depressed by tumour burden. The influence of cimetidine treatment was equivocal being dependent upon time after tumour implantation and dose of mitogen. In this mouse-tumour system, the mechanism of the antimetastic effect of cimetidine is different from that previously suggested [29].
Similar content being viewed by others
References
Adams, III, G. K., and Lichtenstein, L., 1979, In vitro studies of antigen-induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea-pig and human airways to antigen. Journal of Immunology, 122 555–562.
Badger, A. M., Griswold, D. E., Dimartino, M. J., and Poste, G., 1982, Inhibition of antibody synthesis by histamine in concanavalin A-treated mice: the possible role of glucocorticosteroids. Journal of Immunology, 129 1017–1022.
Ballet, J. J., and Merler, E., 1976, The separation and reactivity in vitro of a subpopulation of human lymphocytes which bind histamine. Correlation of histamine reactivity with cellular maturation. Cellular Immunology, 24 250–269.
Benditt, E. P., Wong, R. L., Abase, M., and Roeper, E., 1955, 5-Hydroxytryptamine in mast cells. Proceedings of the Society for Experimental Biology and Medicine, 90 303–304.
Brown, A. E., Badger, A. M., and Poste, G., 1982, The effect of cimetidine on immune cell function and host response to tumours. Current Concepts in Human Immunology and Cancer Immunomodulation, edited by B. Serrou, C. Rosenfield, J. C. Daniels and J. P. Saunders (Amsterdam: Elsevier Biomedical Press), pp. 513–519.
Cochran., A. J., 1978, In vitro testing of the immune response. Immunological aspects of cancer, edited by J. E. Castro (Lancaster: MPT Press Ltd.), pp. 219–266.
Collins, M., and Hellmann, K., 1982, Histamine receptor antagonism and antitumour activity. British Journal of Cancer, 46 817–820.
Dorr, R. T., and Alberts, D. S., 1982, Cimetidine enhancement of cyclophosphamide antitumour activity,. British Journal of Cancer, 43 35–43.
Feldberg, W., 1956, Distribution of histamine in the body. Ciba Foundation Symposium on Histamine, edited by G. E. W. Wolstenholme (London: J. & A. Churchill Ltd.), p. 4.
Finney, D. J., 1964, Statistical Method in Biological Assay. Second edition (London: Griffin).
Freireich, E. J., Gehan, E. A., Ball, D. P., Schmidit, L. H., and Skipper, H. E., 1966, Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemotherapy Reports, 50 219–244.
Friedman, H., Specter, S., Watanabe, M., and Pan, S.-H., 1978, Tumour-induced immunosuppression. American Journal of Pathology, 93 499–513.
Gifford, R. R. M., Ferguson, R. M., and Voss, B. V., 1981, Cimetidine reduction of tumour formation in mice. Lancet, i 638–640.
Hebert, J., Beaudoin, R., Aubin, M., and Fontaine, M., 1980, The regulatory effect of histamine on the immune response: characterization of the cells involved. Cellular Immunology, 54, 49–57.
Hebert, J., Beaudoin, R., Fontaine, M., and Fradet, G., 1981, The regulatory effect of histamine on the immune response. II Effect on the in vitro IGG synthesis. Cellular Immunology, 58, 366–371.
Heidenreich, W., Jagla, K., Schussler, J., Borner, P., Dehnhard, F., Kalden, J. R., Leibold, W., Peter, H. H., and Deicher, H. 1979, Spontaneous cell-mediated cytotoxicity (SCMC) and antibody-dependent cellular cytotoxicity (ADCC) in peripheral blood and draining lymph nodes of patients with mammary carcinoma. Cancer Immunology and Immunotherapy, 7, 65–69.
Hellmann, K., and Burrage, K., 1969, Control of malignant metastases by ICRF 159. Nature, 224, 273–275.
Henney, C. S., Bourne, H. R., and Lichtenstein, L. M., 1972, The role of cyclic 3′, 5′-adenosine monophosphate in the specific cytolytic activity of lymphocytes. Journal of Immunology, 108, 1526–1534.
Jones, B., and Camplejohn, R. S., 1983, Stathmokinetic measurement of tumour cell proliferation in relation to vascular proximity. Cell Tissue Kinetics, 16, 351–355.
Keller, R., 1957, Histamin and 5-hydroxytryptamin in den gewebemastzellen der albinoratte. Helvetica Physiologica et Pharmacologica Acta, 15, 371.
Khangura-Sjogren, H. K., 1981, Characterization of lymphokine-induced inflammation in the guinea pig. Ph.D. Thesis. University of London.
Martinez, J. D., Santos, J., Stechschulte, D. J., and Abdou, N. I., 1979, Non specific suppressor cell function in atopic subjects. Journal of Allergy and Clinical Immunology, 64, 485–490.
Melmon, K. L., 1981, Autacoids as modulators of the immune process: a possible therapeutic strategy. Advances in Immunopharmacology, edited by J. Hadden, L. Chedid, P. Mullen and F. Spreafico (Oxford: Pergamon Press), pp. 267–275.
Meretey, K., Room, G., and Maini, R. N., 1981, Effect of histamine on the mitogenic response of human lymphocytes and its modification by cimetidine and levamisole. Agents and Actions, 11, 84–88.
Morley, J., Wolstencroft, R. A., and Dumonde, D. C., 1978, Measurement of lymphokines. Handbook of Experimental Immunology, Third edition, edited by D. M. Weir (Oxford: Blackwell Scientific Publications), pp. 27.1–27.28.
Mulder, J. H., 1980, Methods of immunogenicity testing of solid tumours in mice: A comparison of the results. British Journal of Cancer, 41, Suppl. IV, p. 160.
Mullen, P. W., 1980, Recent developments in immunopharmacology. Trends in Pharmacological Sciences, 1, 352–354.
Nias, A. H. W., Chamberlain, S. M., and Abdelaal, A. S., 1980, The serially transplanted C3H mouse mammary tumour as a clinically relevant model system. British Journal of Cancer, 41, Suppl. IV, p. 157.
Osband, M. E., Shen, Y.-J., Shlesinger, M., Brown, A., Hamilton, D., Cohen, E., Lavin, P., and McCaffrey, R., 1981, Successful tumour immunotherapy with cimetidine in mice. Lancet, i, 636–638.
Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J., and Smith, P. G., 1977, Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II Analysis and examples. British Journal of Cancer, 35, 1–39.
Reichman, B. L., Handzel, Z. T., Segal, S., Weinstein, Y., and Levin, S., 1979, Participation of a histamine -sepharose-adherent subpopulation of human mononuclear cells in the production of leucocyte migration inhibition factor (LIF) in healthy children. Clinical and Experimental Immunology, 37, 562–566.
Rocklin, R. E., 1976, Modulation of cellular-immune responses in vivo and in vitro by histamine receptor-bearing lymphocytes. Journal of Clinical Investigation, 57, 1051–1058.
Rocklin, R. E., 1977, Histamine-induced suppressor factor (HSF): effect on migration inhibitory factor (MIF) production and proliferation. Journal of Immunology, 118, 1734–1738.
Rocklin, R. E., Greineder, D., Littman, B. H., and Melmon, K. L., 1978, Modulation of cellular immune function in vitro by histamine receptor-bearing lymphocytes: mechanism of action. Cellular Immunology, 37, 162–173.
Scott, O. C. A., 1980, The choice of experimental tumour systems. British Journal of Cancer, 41, Suppl, IV., 112–117.
Shearer, G. M., Melmon, K. L., Weinstein, Y., and Sela, M., 1972, Regulation of antibody response by cells expressing histamine receptors. Journal of Experimental Medicine, 136, 1302–1307.
Tozer, G. M., Penhaligon, M., and Nias, A. H. W., 1984, The use of ketamine and diazepam anaesthesia to increase the radiosensitivity of a C3H mouse mammary adenocarcinoma in hyperbaric oxygen. British Journal of Radiology, 57, (1).
Valentine, M. D., Bach, M., Stechschulte, D. J., and Austen, K. F., 1976, Anaphylactic release of histamine from rat mast cells. Immunology and Immunochemistry V, edited by C. A. Williams and M. W. Chase (New York: Academic Press), pp. 108–114.
Walker, A., McCallum, H. M., Wheldon, T. D., Nias, A. H. W., and Abdelaal, A. S., 1978, Promotion of metastasis of C3H mouse mammary carcinoma by local hyperthermia. British Journal of Cancer, 38, 561–563.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Penhaligon, M., Anthoons, J., Pilkington, D. et al. Antimetastatic effect of cimetidine on mice bearing a C3H mouse mammary adenocarcinoma: survival and lymphocyte function studies. Clin Exp Metast 2, 37–53 (1984). https://doi.org/10.1007/BF00132305
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00132305