Interstrand DNA crosslinking induced by anthracyclines in tumour cells

Using a new mild method it is shown for two anthracyclines, Adriamycin and Daunomycin, that these compounds are able to form DNA crosslinks in HeLa S3 cells. It was also found that other anthracyclines: Epirubicin, Rubidazone, Iodorubicin, 3'-deamino-3'-hydroxy-4'-amino-Adriamycin, Aclacinomycin, Marcellomycin, and Cinerubin A, induced crosslinks in the DNA of HeLa S3 cells in a concentration-dependent manner. DNA crosslinks formed by five anthracyclines studied, excluding Iodorubicin, were both alkali and thermally unstable. No DNA crosslinking could be detected when the compounds were added to cell lysates in which cellular enzymes had been inactivated. This implies that metabolic activation is prerequisite for DNA crosslinking by anthracyclines. The kinetics of DNA crosslinks formation by Adriamycin as well as their removal from cellular DNA were also studied. The presented results indicate that all biologically active anthracyclines studied induce DNA crosslinks, and for two of them DNA crosslinking was observed at growth inhibitory concentrations.