Characterization of daunorubicin resistance in K562 leukemia cells lacking daunorubicin reductase activity.

Daunorubicin (D1)-resistant cells have been isolated from daunorubicin reductase-deficient K562 cells, hence, metabolism of D1 to the alcohol metabolite daunorubicinol (D2) will not contribute to the development of resistance. The resistant cell lines were 22-123-fold resistant and were cross-resistant to a variety of drugs. Drug uptake and efflux were altered in the more resistant lines but not in the less resistant cells. Verapamil enhanced D1 cytotoxicity in all resistant lines; it inhibited D1 efflux in the higher resistant line thereby resulting in an increase in the cellular level of D1. However, this was not true for the less resistant line suggesting that verapamil enhancement of D1 toxicity in the less resistant line is probably due to other factors. Additionally, we have been unable to identify a marker glycoprotein in resistant cells. The changes observed in the resistant sublines are moderate and probably drug accumulation differences could not account for the degree of D1 resistance noted, nor could resistance be wholly reversed by calcium antagonist. Other factors may be involved in the development of resistance in these human cells.