INDUCTION OF APOPTOSIS IN BLOOD-CELLS FROM A PATIENT WITH ACUTE MYELOGENOUS LEUKEMIA BY SC41661A, A SELECTIVE INHIBITOR OF 5-LIPOXYGENASE

Participation of leukotriene products in normal ex vivo hematopoiesis is well established. With increasingly specific inhibitors of lipoxygenases, it becomes possible to more closely define any participation of their biosynthetic products in these events. We cultured chronic myelogenous leukemia cells from the peripheral blood of several patients in blast crisis with three inhibitors of lipoxygenases: ETYA, and the more selective A63162 (Abbott) or SC41661A (Searle). All three agents reduced labelling of DNA with H-3 thymidine measured at 4 h and reduced cell numbers by 72 h. An antisense deoxyoligonucleotide to the 5-lipoxygenase mRNA 'start' codon inhibited DNA synthesis at 24 h, as did two control oligonucleotides. Marked nuclear ultrastructural changes characteristic of apoptosis were induced by SC41661A in a subset of cells with the ultrastructure of promyelocytes. Whether this response characterizes a common pattern of this subset of leukemic cells to SC41661A, if damage to mitochondria with reduced function of bcl-2 protooncogene product located at that site might have contributed or some other mechanism was responsible, and if inhibition of 5-lipoxygenase activity was involved, are questions to be decided in the future.