Lack of cross-resistance of a doxorubicin-resistant B16 melanoma line with 4'-deoxy-4'-iodo-doxorubicin

Abstract

A B16 melanoma cell line in which resistance to doxorubicin (Dx) had been induced by in vitro exposure to the drug, was found not to be cross-resistant with 4'-deoxy-4'-iodo-doxorubicin (4'-I-Dx), a new Dx derivative. Dx was 200 times less active in resistant than in sensitive cells, whereas the iodo derivative compound had the same level of activity in both cell lines. Cytotoxicity of Dx was dependent on concentration and on length of treatment, whereas that of 4'-I-Dx was correlated only with drug concentration. In an effort to explain this different behavior, intracellular retention and distribution of the two drugs was examined. Uptake and efflux of 4'-I-Dx in sensitive and resistant cells were similar, and cellular retention of the drug was 5-25 times higher than that of Dx. In addition, intracellular distribution of the iodo-derivative compound was similar in both cell lines, whereas more nuclear Dx was found in sensitive than in resistant cells. These differences may explain not only the lack of cross-resistance, but also the different cytotoxic behavior, of 4'-I-Dx.