Effect of lysosomotropic and membrane active substances on adriamycin uptake and histamine release

It has recently been shown that adriamycin is accumulated in mast cells by an active transport system, which closely resembles the outward transport system of multidrug resistant (MDR) cells. The present study was undertaken in order to test the effect of substances which are known to limit or reverse resistance in MDR cells on adriamycin uptake and histamine release in rat peritoneal mast cells. The lysosomotropic amines chloroquine, nicotine, propranolol, atropine, methylamine, ammonium chloride and quinacrine were only slightly effective at very high concentrations; no effect could be observed with the lysosomotropic amine amantadine. The carboxylic ionophores monensin and nigericin were, on the contrary, extremely efficacious; in particular, the effect of monensin was more evident when mast cells were preincubated with the ionophore for 10 or 30 minutes while only a slight inhibition was evident when the two substances were added simultaneously. Removal of monensin from the incubation medium before challenge with adriamycin did not abolish the inhibitory action of the ionophore. Among the tested membrane active agents, Tween 80 and Triton WR-1339 were able to limit adriamycin uptake and histamine release. The microscopical examination showed that in mast cells treated with adriamycin, an intense fluorescence was present in cytoplasmic granules; on the contrary, mast cells preincubated with monensin showed hardly any fluorescence.