Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells.
The capacity of doxorubicin to inhibit topoisomerase II in the MCF-7 breast tumor cell line is supported by the induction of protein-associated single-strand breaks in DNA, as well as by interference with the decatenation activity of nuclear extracts. Doxorubicin also produces non-protein-associated DNA strand breaks (at a supraclinical concentration of 5 microM), which may indicate damage mediated via the generation of free radicals. However, no strand breaks are detected in DNA of MCF-7 cells at the IC50 for doxorubicin (approximately 0.1 microM). At doxorubicin concentrations of 0.05, 0.1, and 0.5 microM, at which growth is inhibited by approximately 15, 50, and 75%, respectively, doxorubicin interferes with radiation-induced unwinding of DNA; doxorubicin also produces a concentration-dependent inhibition of DNA synthesis that corresponds closely to growth inhibition. These studies suggest that DNA strand breaks fail to fully account for the antiproliferative activity of doxorubicin in the MCF-7 breast tumor cell line. Compromised DNA synthesis associated with interference with DNA unwinding may contribute to growth inhibition in MCF-7 cells exposed to doxorubicin.
Fornari
F A
FA
Department of Medicine, Medical College of Virginia, Richmond 23298.
Randolph
J K
JK
Yalowich
J C
JC
Ritke
M K
MK
Gewirtz
D A
DA
D001943:Breast Neoplasms; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D006131:Growth Inhibitors; D006801:Humans; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D004278:DNA, Superhelical; D006131:Growth Inhibitors; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II