Barton K, Randall G, Sagone A L
Department of Internal Medicine, Ohio State University, Columbus 43210.
Invest New Drugs. 1989 Jul;7(2-3):179-88. doi: 10.1007/BF00170855.
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.
狼毒素是从瑞香属植物中分离出的最具活性的抗肿瘤化合物，其结构与从巴豆油中分离出的主要活性化合物佛波酯（PMA）相似。已知PMA具有促肿瘤活性，是一种强效炎症介质。据报道，狼毒素同样具有强效炎症特性，但似乎是一种比PMA弱的肿瘤促进剂。虽然PMA对人体血细胞功能和代谢的影响已得到广泛研究，但关于狼毒素的类似信息却很少。因此，在这些研究中，我们比较了狼毒素和PMA在体外激活人粒细胞（PMN）、单核细胞、淋巴细胞和单核细胞（淋巴细胞和单核细胞）培养物的细胞毒性能力和氧化代谢的能力。狼毒素刺激PMN的氧化代谢的方式与PMA相同，HMPS途径活性的爆发、H2O2、羟基自由基和稳定氧化剂的产生表明了这一点。狼毒素还刺激了PMN释放血栓素B2。两种化合物都激活了单核细胞的氧化代谢，但没有激活淋巴细胞的氧化代谢。吞噬细胞氧化代谢增强与对氧化损伤敏感的人红细胞的细胞毒性增加有关，但对NK抗性的拉吉淋巴母细胞系或SW1116结肠肿瘤细胞系没有影响。有趣的是，狼毒素并没有显著增强单核细胞、单核细胞或新鲜分离的淋巴细胞培养物对我们实验中使用的肿瘤细胞靶标的最小细胞毒性能力（NK活性）。然而，用狼毒素预孵育15小时的淋巴细胞培养物对肿瘤靶标的细胞毒性有显著增强。在同样处理的单核细胞培养物中未观察到这种激活作用，这表明单核细胞具有抑制活性。我们的数据表明，狼毒素与PMA相似的强效炎症活性可能与其激活吞噬细胞氧化和花生四烯酸代谢的能力有关。此外，狼毒素激活淋巴细胞细胞毒性能力可能与其在体内的抗肿瘤活性有关。
