DNA damage and cytotoxicity induced by metabolites of anthracycline antibiotics, doxorubicin and idarubicin.
This study assessed the ability of major metabolites of two types of anthracycline antibiotics, doxorubicin and idarubicin (4-demethoxydaunorubicin) to damage DNA in mouse fibrosarcoma 935.1 cells. Since DNA lesions by anthracyclines may be mediated by topoisomerase II, we also characterized the ability of the drugs to inhibit this enzyme. The C-13 alcohol and aglycone metabolites of doxorubicin and idarubicin were compared to the parent drugs in terms of induction of DNA single strand breaks measured by filter elution. In whole cells, the maximal DNA strand breakage induced by the C-13 alcohol metabolites was similar to that of their respective parent drugs. In isolated nuclei, however, the alcohol metabolites were two times more potent than the parent drugs. The aglycone metabolites produced very little damage in either whole cells or nuclei. The doxorubicin compounds differed markedly from idarubicin drugs in the way their ability to induce DNA breaks was related to cytotoxic activity. Doxorubicin and doxorubicinol cytotoxic effects (50% cell growth inhibition at 0.2 and 4 microM, respectively) coincided (in terms of drug concentrations) with the induction of significant breakage of cellular DNA. In contrast, the concentrations of idarubicin and idarubicinol needed to produce 50% growth inhibition (0.005 and 0.006 microM, respectively) were about 20 times lower than drug levels that induced significant DNA damage. All six compounds inhibited the catalytic activity of isolated topoisomerase II. While the alcohol metabolites produced this inhibition at concentrations similar to those of their parent drugs (5-10 microM), the aglycones were again much less active.(ABSTRACT TRUNCATED AT 250 WORDS)
Ferrazzi
E
E
Roswell Park Cancer Institute, Grace Cancer Drug Center, Buffalo, NY 14263.
Woynarowski
J M
JM
Arakali
A
A
Brenner
D E
DE
Beerman
T A
TA
D000818:Animals; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000633:toxicity*; D005354:Fibrosarcoma / Q000235:genetics; D015255:Idarubicin / Q000031:analogs & derivatives / Q000633:toxicity*; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004273:DNA, Neoplasm; D004317:Doxorubicin; D015255:Idarubicin