Cellular pharmacology of 7(R)-O-methylnogarol: a new anticancer agent

Abstract

The cellular accumulation and disposition of 7(R)-O-methylnogarol (7-OMEN), a derivative of the anthracycline antibiotic, nogalamycin, were compared to those of daunorubicin. Although both drugs were avidly accumulated by cells, intracellular concentrations of 7-OMEN were 5 to 10 times those of daunorubicin. Lowered temperature (0 degrees C) reduced intracellular accumulation of both drugs, but 10 mM sodium azide reduced the accumulation of 7-OMEN only. Both drugs exited from cells placed in drug-free medium, a process that was reduced at 0 degrees C. Sodium azide, 10 mM, did not alter the efflux of daunorubicin from cells but hastened the efflux of 7-OMEN. Unlike whole cells, isolated nuclei accumulated more daunorubicin than 7-OMEN. This process was not reduced at 0 degrees C. Both drugs were lost from nuclei placed in drug free buffer with only slight reduction at 0 degrees C. Unlike daunorubicin which localized in cell nuclei, 7-OMEN localized in the cytoplasm with no detectable nuclear fluorescence. Both drugs produced nearly equivalent dose-dependent inhibition of [3H]thymidine incorporation by L1210 and P388 cells. P388/ADR cells proved resistant to both anthracyclines. [3H]uridine and [3H]valine incorporations were inhibited by daunorubicin but were not altered by 7-OMEN.