Indomethacin modulation of adriamycin-induced effects on multiple cytolytic effector functions

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.