Novel Mechanism of N‐Solanesyl‐N,N′‐bis(3,4‐dimethoxybenzyl)ethylenediamine in Potentiation of Antitumor Drug Action on Multidrug‐resistant and Sensitive Chinese Hamster Cells

The mechanism of the synthetic isopremoid N‐solanesyl‐N,N′‐bis(3,4‐dimethoxybenzyl)ethylenediantine (SDB‐ethylenediamine) in potentiating antitumor drug action against multidrug‐resistant cells was comparatively studied with other potentiators such as verapamil and cepharanthine. SDB‐ethylenediamine increased the accumulation of [(3)H]daunorubicin (DNR) in Chinese hamster V79 (V79/S) and its multidrug‐resistant mutant (V79/ADM) cells. Even after SDB‐ethylenediamine was removed from the medium, its effect continued. But when verapamil was removed from the medium, its effect disappeared immediately. Unlike verapamil and cepharanthine, SDB‐ethylenediamine did not greatly inhibit the efflux of [(3)H]DNR from V79/ADM, the binding of [(3)H]vinblastine to membrane vesicles of V79/ADM, or the binding of [(3)H]azidopine to P‐glycoprotein in the cytoplasmic membrane of V79/ADM. It did stimulate the influx of [(3)H]DNR into the ATP‐depleted cells of V79/S and V79/ADM. Thus, SDB‐ethylenediamine uniquely potentiates antitumor drugs. The increased intracellular accumulation of antitumor drugs in the presence of SDB‐ethylenediamine is due not only to the inhibition of active efflux but also to the stimulation of the influx of antitumor drugs.