EPOXIDE METABOLITE OF QUININE AND INHIBITION OF THE MULTIDRUG-RESISTANCE PUMP IN HUMAN LEUKEMIC LYMPHOBLASTS

Multidrug resistance (MDR) in neoplastic cells is usually due to decre ased cellular retention of drugs such as vincristine or doxorubicin. A n ATP-dependent drug efflux pump has been detected in MDR-1-phenotypic cells; inhibition of the MDR pump is probably the primary mechanism f or reversal of MDR. Although quinine (SQ1) and quinidine are reversal agents and inhibitors of the MDR pump, the results from in vivo experi ments and in vitro experiments with these diastereomers are contradict ory. These observations suggest that an oxidized metabolite of SQ1 is a more potent inhibitor of the MDR pump than is the parent compound. T he chemical synthesis of the epoxides of SQ1 and quinidine is reported . The epoxy compounds have been tested as inhibitors of the ATP-depend ent MDR pump in human CEM/VLB(100) cells. The procedure is based on pr eloading the cells with an inhibitor and a low concentration of a subs trate, rhodamine 123 (R123). After several cold rinses, the cell suspe nsion is passed through a filtration-flow apparatus and the R123 in th e filtrate (determined by fluorescence measurements) reveals the initi al efflux of R123 through the MDR pump. When tested as an inhibitor of the MDR pump, quinine-10,11-epoxide is approximately 8-fold more pote nt than SQ1.