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 distribution of the anthracycline antibiotics doxorubicin (DR) and carminomycin (CM) in the free forms or within conjugates with the epidermal growth factor (EGF) were for the first time compared in human breast carcinoma cell lines MCF-7Wt and MCF-7AdrR. The cytotoxic activities of DR and CM conjugates with EGF were higher than the cytotoxic activities of the free antibiotics in both cell lines. The accumulation levels of the free anthracyclines in both cell lines were lower than those of the conjugates and significantly depended on the cell sensitivities to the antibiotics. On receptor-mediated endocytosis of the anthracycline-EGF conjugates, the accumulation levels did not significantly depend on the cell sensitivities to the antibiotics. Both DR and CM, either free or conjugated with EGF, were mainly accumulated in nuclei. The free drugs were accumulated more rapidly, and the accumulation rates of both free and EGF-conjugated CM were higher than those of DR preparations. The intracellular distribution of the free antibiotics significantly depended on the cell sensitivities to the anthracyclines, whereas the cell sensitivities had no effect on the distribution of the conjugates 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 accumulation 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.
Lutsenko
S V
SV
Moscow Research Institute of Medical Ecology, Moscow, 113149, Russia.
Feldman
N B
NB
Gumanov
S G
SG
Rodina
A V
AV
Severin
S E
SE
D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004815:Epidermal Growth Factor; D004317:Doxorubicin