A TEST SYSTEM FOR LEUKOTRIENE SYNTHESIS INHIBITORS BASED ON THE IN-VITRO DIFFERENTIATION OF THE HUMAN LEUKEMIC-CELL LINES HL-60 AND MONO-MAC-6

Differentiation of HL-60 cells along the granulocytic lineage by DMSO in the presence of transforming growth factor-P and low concentrations of 1,25-dihydroxy-vitamin D-3 leads to the upregulation of 5-lipoxyge nase activity in 100,000 g supernatants and intact cells to levels whi ch are comparable to normal granulocytes. Similarly, differentiation o f the human monocytic cell line Mono Mac 6 by 1,25-dihydroxyvitamin D- 3 and transforming growth factor-beta strongly upregulates the 5-lipox ygenase pathway. Here, we describe an assay system for leukotriene bio synthesis inhibitors which is based on the in-vitro differentiation of HL-60 and Mono Mac 6 cells. Different leukotriene biosynthesis inhibi tors like the nonredox type inhibitor ZM 230487, the redox type inhibi tor BW A4C and the FLAP inhibitor MK886 were tested and the results we re compared with an assay system based on normal human granulocytes. Z M 230487, BWA4C and MK886 showed similar potencies in these cell lines as compared to normal leukocytes. Thus, the in-vitro differentiation of HL-60 and Mono Mac 6 cells provides an excellent model for the scre ening of drugs affecting the 5-lipoxygenase pathway.