Synergistic enhancement of mitogen responses of human lymphocytes by inhibitors of cyclo-oxygenase and lipoxygenase.

Previously we reported that inhibitors of the enzyme cyclo-oxygenase, which reduce biosynthesis of prostaglandins, may enhance mitogenic responses of human blood lymphoid cells, whereas only marginal effects were observed with 5,8,11-eicosatriynoic acid (ETI), which inhibits 12-lipoxygenase and leukotriene biosynthesis. However, sharply enhanced mitogen responses were observed when lymphoid cells were cultured with both a cyclo-oxygenase inhibitor and ETI, suggesting a synergy between the two drugs. To test whether this is a more general phenomenon occurring between inhibitors of cyclo-oxygenase and lipoxygenase, we have now extended these studies to include the following lipoxygenase inhibitors: cirsiliol; esculetin; 5,8,11,14-eicosatetraynoic acid, and nordihydroguaiaretic acid. The results have shown that any of these drugs combined with a cyclo-oxygenase inhibitor may enhance mitogen responses more than one would expect by summing the effects of the inhibitors tested separately. We conclude that inhibitors of cyclo-oxygenase and lipoxygenase may synergistically enhance mitogen responses of lymphoid cells.