DOES ADRIAMYCIN INDUCE INTERSTRAND CROSS-LINKS IN DNA

Under nonenzymatic conditions in vitro, Adriamycin appears to form interstrand cross-links with DNA over 1-2 days. This is the first report of such Adriamycin-induced interstrand cross-links in vitro. Cross-links were measured by a fluorescence based renaturation assay and also by gel electrophoresis. Both procedures revealed an increase of cross-linking with reaction time and with increasing Adriamycin concentration and a 5-6-fold enhancement in the presence of Fe3+ ions. The cross-link contains the Adriamycin chromophore, with a lambda(max) of 508 nm, intercalated at the GpC site of cross-linking. Maximal stoichiometry of the cross-link was one per 11-20 bp. The cross-link appears to involve adducts of the Adriamycin chromophore linked to the N-2 of guanine, with no indication that N-7 of guanine is involved. Given that the mode of action of Adriamycin still remains obscure, even after 20 years of clinical use, the possibility that interstrand DNA cross-links may be associated with the clinical mechanism of action of this drug should now be fully addressed.