SELECTIVE INHIBITORS OF 5-LIPOXYGENASE REDUCE CML BLAST CELL-PROLIFERATION AND INDUCE LIMITED DIFFERENTIATION AND APOPTOSIS

Inhibitors of the arachidonic acid metabolizing enzyme, 5-lipoxygenase , reduce the rate of proliferation of chronic myelogenous leukemia bla st cells. The inhibitory agents studied were ETYA, A63162 and SC41661A . These reagents induced differentiation of cultured chronic myelogeno us leukemia cells from blast to promyelocytic morphology. Promyelocyti c cells then underwent apoptosis, which was identified by nuclear and cytoplasmic morphological features and by DNA laddering. Proliferation of monoblastoid U937 and myelomonocytic HL60 cell lines, known to con tain 5-lipoxygenase and synthesize leukotrienes, was reduced by these inhibitors. U937 cells cultured with ETYA, A63162 or SC41661A for 48 h exhibited apoptosis as assessed by DNA laddering and morphology. Char acteristic ultrastructural changes of apoptosis were seen at 120 h, MK 886, an inhibitor of 5-lipoxygenase with a mechanism of action distinc t from oxidation/reduction reagents, at 20-40 mu M also inhibited CML and U937 cell proliferation and induced apoptosis, as shown by DNA lad dering and ultrastructure.