Cellular pharmacology of doxorubicin in sensitive and resistant rat glioblastoma cells in culture.

We have studied the incorporation and cytotoxicity of doxorubicin in cultured rat C6 glioma cells grown as monolayers. Net incorporation was linear up to high extracellular concentrations of drug (10 micrograms/ml). Cytotoxicity was evaluated both by tritiated thymidine incorporation inhibition and cloning efficiency inhibition. For similar total drug exposures, cytotoxicity was very different according to the exposure time and the exposure dose; incubation with a low dose for a long time was much less cytotoxic than that performed with a high dose for a short period of time. We have obtained several clones of doxorubicin-resistant cells. As compared to the wild strain, these cells were characterized by a larger size, a slower growth, a reduced cloning efficiency and a differential sensitivity of 100-1,000 to doxorubicin. Net incorporation of doxorubicin was 5-fold reduced in these cells, due to an increased efflux of the drug. These cells provide an interesting model of doxorubicin-resistant solid tumor in culture.