Circumvention of resistance to daunorubicin by N-acetyldaunorubicin in Ehrlich ascites tumor.

Experimental evidence indicates that Ehrlich ascites tumor cells resistant to daunorubicin (DNR) have a higher active drug extrusion than do wild-type cells. In the present study, the possibility of circumventing this mechanism of resistance by addition of an analog of DNR, N-acetyldaunorubicin (N-acetyl-DNR), was investigated in vitro and in vivo. The affinity of N-acetyl-DNR was 7 times lower than that of DNR in the lysates of both wild-type and resistant cells. In agreement with this finding, N-acetyl-DNR reduced the binding of [3H]DNR to lysate from the two cell lines only to a minor extent. On the other hand, N-acetyl-DNR exerted a marked inhibition on both the active efflux and the unidirectional influx of [3H]DNR in both cell lines. Within certain limits, addition of N-acetyl-DNR resulted in increased steady-state uptake of [3H]DNR; in wildtype cells, the maximal obtainable elevation was 18%, compared to 142% in resistant cells. In vivo addition of N-acetyl-DNR, even at 80 mg/kg for 4 consecutive days, did not influence the toxicity of DNR in mice. In a therapeutic experiment, addition of N-acetyl-DNR increased the antitumor activity of DNR upon the resistant tumor line significantly, but no change was observed in the wild-type tumor. These data indicate that N-acetyl-DNR or related analogs may be used as adjuvants to circumvent acquired resistance to DNR.