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

Abstract

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.

The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis

“…Of interest is that our study used a lower dose (0.03%) of SM16 than the 0.045% dose that was shown to inhibit primary tumor growth in previous studies [19–23]. This lower dose of SM16 is likely to be less toxic and therefore could be of greater clinical utility [43]. At 0.03% in feed, equivalent to ~0.9mg/day, SM16 by itself resulted in only 23% tumor growth reduction, however we observed tumor regression in 6% of the mice.…”

Pivotal Role of Innate and Adaptive Immunity in Anthracycline Chemotherapy of Established Tumors

“…Doxorubicin became the most widely used anthracycline because of lower toxicity and potent antitumor activity against solid tumors. Although there were earlier reports evidencing the immune system contribution to doxorubicin-mediated antitumor effects (11,12), Maccubbin and colleagues were the first to show that doxorubicin was an effective immunomodulator capable of boosting CTL responses (13). A multitude of studies investigating combination treatment of doxorubicin and immunotherapies followed; however, the underlying mechanisms of how immunogenic cell death caused by doxorubicin links to induction of a cytotoxic CD8 T-cell response were largely unknown.…”

Anticancer Drug-Induced Immunomodulation and Cancer Therapeutics

“…DOX also affected NK and Lymphokine Activated Killer (LAK) cells causing either their stimulation [89,[97][98][99] or inhibition [79,[97][98][99][100] depending on conditions, as it might be expected of an immunomodulating agent. DOX was found to augment maturation and activation of macrophages with resulting increases of accessory functions in a sheepred-blood-cell system [101], of phagocytosis [102] and of production of IL1, prostaglandin E (PGE 2 ) and TNF [97,103].…”

“…DOX was found to augment maturation and activation of macrophages with resulting increases of accessory functions in a sheepred-blood-cell system [101], of phagocytosis [102] and of production of IL1, prostaglandin E (PGE 2 ) and TNF [97,103]. As mentioned above, the agent has opposite effects on NK cells; it inhibited them in the spleen [97][98][99][100] but augmented them in peritoneal exudates cells (PEC) [97][98][99]. Because the Inhibition of NK in spleen was reversed by Indomethacin [100] it is reasonable to postulate that it was a consequence of the increased production of PGE 2 induced by DOX.…”

“…As mentioned above, the agent has opposite effects on NK cells; it inhibited them in the spleen [97][98][99][100] but augmented them in peritoneal exudates cells (PEC) [97][98][99]. Because the Inhibition of NK in spleen was reversed by Indomethacin [100] it is reasonable to postulate that it was a consequence of the increased production of PGE 2 induced by DOX. Indeed, spleen cells from DOX-treated mice were found to produce a large amount of PGE 2 in culture which was in the same range as the concentration of added PGE 2 required to inhibit NK.…”