Reversal of multidrug resistance by lipophilic drugs

Abstract

The phenomenon of multidrug resistance implies that a wide spectrum of structurally and functionally unrelated chemotherapeutic drugs are recognized and processed by the molecular system which protects multidrug-resistant (MDR) cells against lipophilic cytotoxic drugs. This suggests that lipophilic agents with low toxicity may also be recognized and processed by this molecular system. At high concentrations these agents might saturate the system, thereby reversing multidrug resistance. In support of this hypothesis, 19 (73%) of 26 arbitrarily chosen lipophilic drugs were in this study found to increase the accumulation of actinomycin D in MDR WEHI 164 cells. The most potent of these drugs were also shown to sensitize these cells to the cytotoxic effect of actinomycin D and doxorubicin. There was a good correlation between the ability of the lipophilic drugs to induce an increased accumulation of actinomycin D in MDR cells and their ability to sensitize these cells to the cytotoxic effect of chemotherapeutic drugs. The ability to reverse drug resistance appeared to be additive, since increased accumulation of actinomycin D was also obtained by combining low concentrations of various lipophilic drugs. This may be a way to reduce the in vivo toxic effect of the lipophilic drugs yet still obtain a reversal of drug resistance. When MDR cells were exposed to lipophilic drugs which reversed drug resistance, the synergistic cytotoxic effect of actinomycin D and tumor necrosis factor was obtained at reduced actinomycin D concentrations.