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

摘要

A comparative analysis of cytotoxic activities (CTA), levels, and dynamics of accumulation and mode of intracellular distribution of the anthracycline antibiotics doxorubicin (DR) and carminomycin (CM) has been carried out for the first time. The antibiotics were delivered to target cells (human mammary carcinomas MCF-7~(Wt) and MCF-7~(AdrR) both in the free form and within conjugates with epidermal growth factor (EGF). It was found that DR and CM conjugates with EGF manifested higher CTA against MCF-7~(Wt) and MCF-7~(AdrR) cells in comparison with the free antibiotics. The rates of accumulation of the free anthracyclines in target cells were lower than those of EGF-DR and EGF-CM conjugates and strongly depended on the resistance of the target cells to the effects of the antibiotics. In contrast, in the case of receptor-mediated endocytosis the antibiotic sensitivity of EGF-DR and EGF-CM conjugates was not a crucial factor. Both free DR and CM and their conjugates with EGF were largely accumulated in the nuclei. The free antibiotics were accumulated in target cells at the highest rates, the rates of accumulation of free CM and EGF-CM exceeding those of DR preparations. The mode of intracellular distribution of free DR and CM significantly depended on the sensitivity of the cells to the anthracycline antibiotics, whereas the distribution of conjugates between the nuclei and the cytoplasm did not depend on this factor. 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 differences in the levels and dynamics of accumulation of DR and CM in the cells and the mode of intracellular distribution of these antibiotics (both free and within conjugates with EGF) may be the reason for higher cytotoxity of DR and CM conjugates with EGF in comparison with the free antibiotics,