Comparison of DNA scission and cytotoxicity produced by Adriamycin and 5-iminodaunorubicin in human colon carcinoma cells.
The quinone-modified anthracycline, 5-iminodaunorubicin, which does not spontaneously generate free radicals, was compared to Adriamycin on the basis of DNA-protein crosslink-associated single-strand breakage, cell lethality, and the pharmacokinetics of drug uptake and efflux in human colon carcinoma cells in culture. At equivalent cytocidal concentrations, 5-iminodaunorubicin produced more single-strand breakage of DNA than Adriamycin after a 2-hr treatment interval, but the DNA scission produced by 5-iminodaunorubicin rapidly disappeared after drug removal. The kinetics of DNA breakage correlated with the rapid rates of uptake and efflux of 5-iminodaunorubicin in comparison to Adriamycin. These data emphasize the importance of the cellular pharmacokinetics of anthracyclines in relation to their cytocidal and DNA damaging properties. Moreover, the induction of equivalent single-strand breakage of DNA by similar intracellular concentrations of both drugs suggests that the free radical properties of Adriamycin are not involved in DNA scission.
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics
D004277:DNA, Single-Stranded; D004317:Doxorubicin; D004247:DNA; C018979:5-iminodaunorubicin; D003630:Daunorubicin