Comparative intracellular uptake of adriamycin and 4'-deoxydoxorubicin by non-small cell lung tumor cells in culture and its relationship to cell survival.
4'-Deoxydoxorubicin (4'-deoxy) is a new adriamycin analogue with a similar spectrum of antitumour activity but is significantly more lipophilic than the parent compound. We report the kinetics and uptake of the two drugs by human non-small cell lung tumour cells in monolayer culture and the relationship between intracellular drug levels and cytotoxicity. The rate and degree of cell uptake of 4'-deoxy (Vmax = 30 ng/10(5) cells/min) was greater than that of adriamycin (Vmax = 0.15 ng/10(5) cells/min). Although for a given intracellular drug concentration adriamycin was more lethal, on the basis of extracellular drug concentration, cell kill was virtually identical. The log cell survival vs intracellular drug concentration plot was linear for adriamycin but biphasic for 4'-deoxy. Intracellular distribution of the two drugs was followed by fluorescent microscopy and it was apparent that adriamycin was localized mainly within the nucleus whereas 4'-deoxy accumulated within the cytoplasm. Our results suggest that the relationship between intracellular distribution of the two drugs could reflect different modes of action for the drugs with respect to binding sites or could be a non-specific phenomenon, unrelated to lethal effects.
D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002999:Clone Cells; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000378:metabolism*; D008856:Microscopy, Fluorescence
D004317:Doxorubicin; C030851:esorubicin