Cytotoxic activity, accumulation, and intracellular distribution of anthracycline antibiotics and their conjugates with the epidermal growth factor in sensitive and resistant MCF-7 cells

Cytotoxic activities, accumulation levels and dynamics, and intracellular d istribution of the anthracycline antibiotics doxorubicin (DR) and carminomy cin (CM) in the free forms or within conjugates with the epidermal growth f actor (EGF) were for the first time compared in human breast carcinoma cell lines MCF-7(Wt) and MCF-7(AdrR). The cytotoxic activities of DR and CM con jugates with EGF were higher than the cytotoxic activities of the free anti biotics in both cell lines. The accumulation levels of the free anthracycli nes in both cell hues were lower than those of the conjugates and significa ntly depended on the cell sensitivities to the antibiotics. On receptor-med iated endocytosis of the anthracycline-EGF conjugates, the accumulation lev els did not significantly depend on the cell sensitivities to the antibioti cs. Both DR and CM, either free or conjugated with EGF, were mainly accumul ated in nuclei. The free drugs were accumulated more rapidly, and the accum ulation rates of both free and EGF-conjugated CM were higher than those of DR preparations. The intracellular distribution of the free antibiotics sig nificantly depended on the cell sensitivities to the anthracyclines, wherea s the cell sensitivities had no effect on the distribution of the conjugate s between the nucleus and cytoplasm. The rate of intracellular degradation of DR and CM delivered to target cells within conjugates with EGF was twice lower than that of the free antibiotics. The difference in the accumulatio n levels and dynamics and in the intracellular distribution of the free and conjugated DR and CM is likely to underlie the higher cytotoxic activities of the anthracycline conjugates with EGF compared to the free drugs.