Influence of the extracellular pH, an inhibitor of Na⁺/H⁺ exchanger and an inhibitor of Cl-/HCO₃- exchanger on adriamycin accumulation

We examined the influence of the extracellular pH, an inhibitor of Na⁺/H⁺ exchanger: 3,5-diamino-6-chloro-N-(diaminomethylene) pyrazinecarboxamide (amiloride), and an inhibitor of Cl-/HCO₃^-: 4,4-diisothiocyanatostilbene -2,2-disulfonic acid (DIDS) on the accumulation of adriamycin (ADR) in Ehrlich ascites tumor cells and their adriamycin-resistant strain. A good correlation between the increases in ADR accumulation and the extracellular pH was shown in the both strains. The ADR accumulation decreased with an increasing concentration of amiloride or DIDS in both strains. These findings demonstrate that the influx of ADR was related closely to the efflux of H+ or the activities of Na+/H+ ex-changer and Cl-/HCO3- exchanger. Therefore, rasing either the extracellular pH and enhancement of the activities of either Na+/H+ exchanger or Cl-/HCO3- exchanger may result in the potentiation of the cytotoxic effect ADR through increase of ADR influx.