Cellular pharmacology of 7(R)-O-methylnogarol: a new anticancer agent.
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.
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000378:metabolism; D007942:Leukemia, Experimental / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D008856:Microscopy, Fluorescence; D009279:Naphthacenes / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009621:Nogalamycin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D013050:Spectrometry, Fluorescence
D046911:Macromolecular Substances; D009279:Naphthacenes; D009621:Nogalamycin; D003630:Daunorubicin