Effect of erythromycin and tumour necrosis factor on the drug resistance of multidrug-resistant cells: reversal of drug resistance by erythromycin.

WEHI 164 murine fibrosarcoma cells were rendered multidrug-resistant (MDR) by culture in the presence of actinomycin D. In addition to resistance to actinomycin D, the cells acquired resistance to doxorubicin, mitomycin, vincristine and cycloheximide. The fact that development of resistance to one type of lipophilic chemotherapeutic drug also results in resistance to other structurally unrelated lipophilic drugs suggests that non-toxic lipophilic agents may interfere with drug resistance by saturating the pathway by which MDR-cells inhibit drug cytotoxicity. We show that the antibiotic erythromycin significantly reverses the resistance of MDR WEHI 164 cells to doxorubicin and actinomycin D. In addition to cross-resistance to chemotherapeutic drugs, 3 out of 4 actinomycin D-resistant WEHI 164 cell lines also showed higher resistance to tumour necrosis factor (TNF) than the parental WEHI 164 cells. However, whereas verapamil, a calcium antagonist known to reverse multidrug-resistance, rendered resistant cells more sensitive to chemotherapeutic drugs, it protected the cells from killing by TNF, suggesting that drug resistance and TNF resistance may not be directly connected. A synergistic cytotoxic effect of TNF and actinomycin D was obtained on both the parental and the MDR cells. However, higher concentrations of TNF and actinomycin D were required to obtain a cytotoxic effect in the MDR cells, reflecting actinomycin D and TNF resistance in these cells.