Comparative nuclear and cellular incorporation of daunorubicin, doxorubicin, carminomycin, marcellomycin, aclacinomycin A and AD 32 in daunorubicin-sensitive and -resistant Ehrlich ascites in vitro.

The kinetics of cellular and nuclear incorporation of a number of new anthracyclines into daunorubicin-sensitive and -resistant Ehrlich ascites cells were determined in vitro. For comparative quantitative analyses the substances were extracted with a 0.3 N HCl/50% ethanol (v/v) solution from either whole cells or purified citric acid nuclei after various intervals of in vitro incubation. At steady state the intracellular and intranuclear concentrations of daunorubicin and doxorubicin were reduced by about 50% in the resistant cell line. Marcellomycin and carminomycin concentrations were only reduced by 9% and 11%, respectively, and no differences between sensitive and resistant cells were seen in the case of aclacinomycin A and AD 32. When the ratios of nuclear to cellular drug were determined at steady state lowest value was found for AD 32 (0.26). In contrast, aclacinomycin A and carminomycin were mainly (78% and 74%) and marcellomycin almost exclusively (95%) concentrated in the nucleus. When the total amounts of drug incorporated per cell were compared, the highest values were measured for aclacinomycin A and the lowest for AD 32 both in the sensitive and the resistant tumor. Additional determinations of the 50% inhibitory concentrations for thymidine uptake showed similar differences between these anthracyclines which were not related to the potency of the drugs in vivo. It is concluded that apart from nuclear incorporation and inhibition of DNA synthesis other factors may be decisive for anthracycline-induced cytotoxicity.