Cellular Pharmacokinetics of Doxorubicin in Cultured Mouse Sarcoma Cells Originating from Autochthonous Tumors

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Abstract
We have studied the cellular pharmacology of doxorubicin in a line of mouse sarcoma cells isolated from a dimethylbenzanthracene-induced autochthonous tumor. We have studied the cytotoxicity of the drugs as a function of the exposure dose and of the exposure time to the drug. Cytotoxicity was evaluated as the inhibition of the incorporation of [3H-methyl]-thymidine in the cellular nucleic acids. Intracellular drug concentrations were measured by spectrofluorometry. We have shown that the intracellular drug concentration was a linear function of the extracellular drug concentration up to 5 μg/ml; the cytotoxicity was an exponential function of the exposure dose up to 1 μg/ml, but it was not an exponential function of the exposure time: the cytotoxicity may therefore be very different for similar total drug exposures. Incubation with a low dose for a long time did not provide a cytotoxicity as high as that obtained with a high dose for a short period of time. These results emphasize the role of the peak concentration of doxorubicin for its maximal action in the target cell.

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