Summary
The anticancer agent, Adriamycin (ADM), in addition to being a potent cytotoxic drug has been shown to be an effective immunomodulator. This study was undertaken to determine whether ADM-induced changes in the production of prostaglandins (particularly PGE2) are involved in ADM-associated modifications of selected host defenses. Spleen cells from normal or ADM-treated (5 mg/kg; day −5) C57BL/6 mice were assessed for the following activities: fresh (day 0) and cultured natural killer (NK), cytotoxic T lymphocyte, lymphokine-activated killer (LAK), Fc-dependent phagocytosis and tumoricidal macrophage. All activities were assessed with and without the addition of indomethacin, an inhibitor of the first step of the cyclo-oxygenase pathway of prostaglandin synthesis. Depending on culture conditions, the cytotoxic T lymphocyte and splenic tumoricidal macrophage activities were either unaffected or were augmented by ADM treatment of the spleen donor mice or by addition of indomethacin to the culture, and these effects were apparently independent of one another. In contrast, ADM treatment generally resulted in reduced NK and LAK activities relative to control and elevated Fc-dependent phagocytosis. The addition of indomethacin to the culture effectively reversed these effects. Furthermore, spleen cells from ADM-treated mice were found to produce twice the amount of PGE2 in culture compared to cells from untreated mice. Finally, the direct addition of PGE2 to NK cultures resulted in a dose-dependent inhibition of NK activity and the dose required was comparable to the amount of PGE2 produced by cultured spleen cells from ADM-treated mice. Taken together, these results indicate that at least some of the immunomodulatory effects of ADM are an indirect result of ADM-induced changes in PGE2 production.
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Bachur NR, Gordon SI, Gee MV (1977) Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol 13: 901
Brunda MJ, Herberman RB, Holden HT (1980) Inhibition of murine natural killer cell activity by prostaglandins. J Immunol 124: 2682
Chouaib S, Welte K, Mertelsmann R, DuPont B (1985) Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression. J Immunol 135: 1172
Cohen SA, Ehrke MJ, Mihich E (1975) Mouse effector functions involved in the antibody-dependent cellular cytotoxicity to xenogeneic erythrocytes. J Immunol 115: 1007
Cohen SA, Ehrke MJ, Ryoyama K, Mihich E (1982) Augmentation of the phagocytic activity of murine spleen cell populations induced by Adriamycin. Immunopharmacology 5: 75
Cohen SA, Salazar D, Wicher J (1983) Adriamycin-induced activation of NK activity may initially involve LAF production. Cancer Immunol Immunother 15: 188
Djeu DY, Heinbaugh JA, Vieira WD, Holden HT, Herberman RB (1979) The effect of immunopharmacological agents on mouse natural cell-mediated cytotoxicity and on its augmentation by poly I: C. Immunopharmacology 1: 231
Droller MJ, Perlmann P, Schneider MU (1978) Enhancement of natural and antibody-dependent lymphocyte cytotoxicity by drugs which inhibit prostaglandin production by tumor target cells. Cell Immunol 39: 154
Droller MJ, Schneider MU, Perlmann P (1978) A possible role of prostaglandins in the inhibition of natural and antibody-dependent cell-mediated cytotoxicity against tumor cells. Cell Immunol 39: 165
Ehrke MJ, Ryoyama K, Tomazic V, Cohen SA, Mihich E (1980) Selective imbalances of cellular immune responses by Adriamycin. Recent Results Cancer Res 75: 195
Ehrke MJ, Cohen SA, Mihich E (1982) Selective effects of Adriamycin on murine host defense systems. Immunol Rev 65: 55
Ehrke MJ, Tomazic V, Ryoyama K, Cohen SA, Mihich E (1983) Adriamycin induced immunomodulation: dependence upon time of administration. Int J Immunopharmacol 5: 43
Ehrke MJ, Ryoyama K, Cohen SA (1984) Cellular basis for Adriamycin-induced augmentation of cell-mediated cytotoxicity in culture. Cancer Res 44: 2497
Ehrke MJ, Maccubbin D, Ryoyama K, Cohen SA, Mihich E (1986) Correlation between Adriamycin-induced augmentation of interleukin 2 production and of cell mediated cytotoxicity. Cancer Res 46: 54
Ehrke MJ, Mihich E, Berd D, Mastrangelo MJ (1989) Effects of anticancer drugs on the immune system in humans. Semin Oncol 16: 230
Flower RJ (1974) Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 26: 33
Handa K, Sato S (1975) Generation of free radicals of quinone group containing anticancer chemicals in NADPH-microsome system as evidenced by initiation of sulfite oxidation. Gann 66: 43
Hember ME, Cook HW, Lands WEM (1979) Prostaglandin biosynthesis can be triggered by lipid peroxides. Arch Biochem Biophys 193: 340
Herberman RB (1987) Lymphokine-activated killer activity: characteristics of effector cells and their progenitors in blood and spleen. Immunol Today 8: 178
Hersey P (1973) Macrophage effector function. An in vitro system of assessment. Transplantation 15: 282
Hoffmann CC, Ehrke MJ, Mihich E (1979) Temporal specificity of procarbazine in the inhibition of mouse immune responses to allogeneic tumor. J Immunopharmacol 1: 157
Lala PK, Parhar RS, Singh P (1986) Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis. Cell Immunol 99: 108
Leung KH, Koren HS (1982) Regulation of human natural killing. II. Protective effect of interferon on NK cells from suppression by PGE2. J Immunol 129: 1742
Leung KH, Mihich E (1980) Prostaglandin modulation of development of cell-mediated immunity in culture. Nature 288: 597
Lown JW (1983) The mechanism of action of quinone antibiotics. Mol Cell Biochem 55: 17
Maca RD (1983) The effects of prostaglandins on the proliferation of cultured human T lymphocytes. Immunopharmacology 6: 267
Mace K, Mayhew E, Mihich E, Ehrke MJ (1988) Alterations in murine host defense functions by Adriamycin or liposome-encapsulated Adriamycin. Cancer Res 48: 130
Mantovani A, Luini W, Peri G, Vecchi A, Spreafico F (1978) Effects of chemotherapeutic agents on natural cell-mediated cytotoxicity in mice. J Natl Cancer Inst 61: 1255
Mantovani A, Candiani P, Luini W, Salmona M, Spreafico F, Garattini S (1979) Effects of chemotherapeutic agents on host defense mechanisms: its possible relevance for the antitumoral activity of these drugs. In: Current trends in tumor immunology; Ferrone S, Gorini S, Herberman RB, Reisfeld RA (eds). Garland Press, New York, p 139
Myers CE, McGuire WR, Liss RH, Ifrim I, Grotzinger K, Young RC (1977) Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response. Science 197: 165
Nakata K, Kashimoto S, Yoshida H, Oku T, Nakamura S (1988) Augmented antitumor effect of recombinant human interleukin-1 α by indomethacin. Cancer Res 48: 584
Orsini R, Pavelic Z, Mihich E (1977) Increased primary cell mediated immunity in culture subsequent to Adriamycin or daunorubicin treatment of spleen donor mice. Cancer Res 37: 1719
Ortaldo JR, Mason A, Overton R (1986) Lymphokine-activated killer cells: analysis of progenitors and effectors. J Exp Med 164: 1193
Panje NR (1981) Regression of head and neck carcinoma with a prostaglandin synthesis inhibitor. Arch Otolaryngol 107: 658
Razin E, Bablminger S, Globerson A (1978) Effect of prostaglandins on phagocytosis of sheep erythrocytes by mouse peritoneal macrophages. J Reticuloendothel Soc 23: 237
Salazar D, Cohen SA (1984) Multiple tumoricidal effector mechanisms induced by Adriamycin. Cancer Res 44: 2561
Santoni A, Riccardi C, Sorci V, Herberman R (1980) Effects of Adriamycin on the activity of mouse natural killer cells. J Immunol 124: 2329
Schwartz HS (1983) Mechanisms of selective cytotoxicity of Adriamycin, daunorubicin and related anthracyclines. In: Molecular aspects of anticancer drug action: topics in molecular and structural biology, vol 3. Neidle S, Waring MJ (eds) MacMillan, New York
Tomazic V, Ehrke MJ, Mihich E (1981) Augmentation of the development of immune responses of mice against allogeneic tumor cells after Adriamycin treatment. Cancer Res 41: 3370
Tzung S-P, Gaines KC, Ehrke MJ, Cohen SA (1990) Suppression of lymphokine-activated killer cell induction from murine liver Kupffer cells and hepatocytes. Hepatology (in press)
Venuto RC, O'Dorisio T, Stein JH, Ferris TF (1975) Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit. J Clin Invest 55: 193
Walker C, Kristensen F, Bettens F, deWeck AL (1983) Lymphokine regulation of activated (G1) lymphocytes. I. Prostaglandin E2-induced inhibition of interleukin 2 production. J Immunol 130: 1770
Webb DR, Nowowiejeski I (1977) The role of prostaglandins in the control of the primary 19 s immune response to SRBC. Cell Immunol 33: 1
Young RC, Ozols RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305: 139
Zusman RM, Spector D, Caldwell BN, Speroff L, Schneider G, Mulrow PJ (1971) The effect of chronic sodium loading and sodium restriction on plasma prostaglandins A, E and F concentrations in normal humans. J Clin Invest 52: 1093
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This work was supported in part by USPHS grants CA-28 835, CA-15 142, CA-24 538 and CA-09072 and from Veterans Administration Research Funds
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Maccubbin, D.L., Cohen, S.A. & Ehrke, M.J. Indomethacin modulation of Adriamycin-induced effects on multiple cytolytic effector functions. Cancer Immunol Immunother 31, 373–380 (1990). https://doi.org/10.1007/BF01741409
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DOI: https://doi.org/10.1007/BF01741409