The effects of the anti-tumor agent mezerein on the cytotoxic capacity and oxidative metabolism of human blood cells.

Mezerein, the most active antitumor compound isolated from the daphne species of plants, has a structural similarity to phorbol myristate acetate (PMA), the major active compound isolated from croton oil. PMA is known to have tumor promoting activity and is a potent inflammatory agent. Mezerein has similarly been reported to have potent inflammatory properties but appears to be a weaker tumor promoter than PMA. While the effect of PMA on the function and metabolism of human blood cells has been extensively studied, there is little similar information concerning mezerein. Therefore, in these studies, we have compared the capacities of mezerein and PMA to activate the cytotoxic capacity and oxidative metabolism of human granulocyte (PMNs), monocyte, lymphocyte, and mononuclear cell (lymphocytes and monocytes) cultures in vitro. Mezerein stimulated the oxidative metabolism of PMNs in an identical manner to PMA as indicated by a burst in the activity of the HMPS pathway, the production of H2O2, hydroxyl radical and stable oxidants. Mezerein also stimulated the release of thromboxane B2 from PMNs. Both compounds activated the oxidative metabolism of monocytes but not the oxidative metabolism of lymphocytes. The enhanced oxidative metabolism of the phagocytic cells was associated with an increased cytotoxicity against human red cells which are sensitive to oxidant damage but not against the NK resistant Raji lymphoblast cell line or the SW1116 colon tumor cell line. Of interest is that mezerein did not augment significantly the minimal cytotoxic capacity (NK activity) of mononuclear cells, monocytes or freshly isolated lymphocyte cultures against the tumor cell targets used in our experiments. However, lymphocyte cultures preincubated for 15 hours with mezerein had a marked enhancement of cytotoxicity against the tumor targets. This activation was not observed in similarly treated mononuclear cell cultures suggesting a suppressor activity of the monocytes. Our data suggest that the potent inflammatory activity of mezerein similar to PMA, may be related to its capacity to activate the oxidative and arachidonic metabolism of phagocytic cells. In addition, the capacity of mezerein to activate the cytotoxic capacity of lymphocytes may relate to its reported in vivo antitumor activity.