Comparative cytotoxicity, DNA synthesis inhibition and drug incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat glioblastoma cells

Abstract

We have compared the growth inhibition, DNA synthesis inhibition and cell incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat C6 glioblastoma cells. The anthracyclines studied were both the reference molecules (daunorubicin, doxorubicin) and the new drugs recently introduced in clinical use or in trials (epirubicin, idarubicin, pirarubicin, esorubicin, rubidazone, 4'-deoxy-4'-iododoxorubicin). We have shown that the in vitro growth inhibition was correlated with the 1 ld 50. The new anthracyclines were more potent than the reference drugs in the sensitive cells and the resistance patterns revealed a reduced cross resistance of idarubicin, pirarubicin and 4'-deoxy-4'-iododoxorubicin towards the doxorubicin-resistant line. DNA synthesis inhibition occurred for much higher doses than growth inhibition in sensitive cells, but for similar doses in resistant cells. This suggests that different mechanisms could be involved in the mechanism of growth inhibition in sensitive and resistant cells. For similar exposures, reduction of drug incorporation was a general feature in the resistant line when compared to the sensitive one. However, no correlation was shown, for the various drugs, between the reduction of incorporation and the resistance factor. Moreover, the intracellular concentration required for growth inhibition is much higher in resistant cells than in sensitive cells, suggesting that increased drug efflux might not be the only mechanism to explain drug resistance.