THE LEUKOTRIENE LTD(4) RECEPTOR ANTAGONIST MK571 SPECIFICALLY MODULATES MRP ASSOCIATED MULTIDRUG-RESISTANCE

The multidrug resistant cell lines HL60/AR and GLC4/ADR show high over expression of the gene encoding the multidrug resistance associated pr otein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was pr oven by a complementary DNA polymerase chain reaction (cDNA-PCR) appro ach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we de monstrate on both MDR sublines a dose-dependent modulation of drug res istances by the leukotriene LTD, receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 conce ntrations of 30 mu M (HL60/AR) or 50 mu M (GLC4/ADR) which by itself d id not disturb cellular proliferation. The drug resistance of a mdr1/P -gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using t he glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate trans porter and identify MK571 as a new tool structure for developing modul ators specific for a MRP associated multidrug resistance. (C) 1995 Aca demic Press, Inc.