COMPARISON OF AZA-ANTHRACENEDIONE-INDUCED DNA-DAMAGE AND CYTOTOXICITYIN EXPERIMENTAL TUMOR-CELLS

Aza-anthracenediones are a new class of anti-cancer drugs, which demon strate promising in vitro and ill vivo activity. Our laboratory has sy nthesized a variety of structural analogs in which we determined previ ously that the positioning of the nitrogen within the backbone, as wel l as sidearm modification, results in dramatic differences in the pote ncy of cytotoxicity. We reported previously that although DNA reactivi ty appears to be a necessary component for mediating cell death, it is not sufficient for predicting cytotoxicity of the aza-anthracenedione s. We have chosen three aza-anthracenediones (BBR 2828, BBR 2778 and B BR 2378) to investigate the importance of DNA strand breaks and/or pro tein-concealed DNA breaks induced by aza-anthracenediones. We determin ed in the present study that, while all three drugs cause DNA breaks a s determined by alkaline and neutral elution, as well as KCI-SDS preci pitation, these breaks do not correlate directly with their potency as cytotoxic compounds. Further, we found significant differences in the types of DNA breaks induced by these drugs. Finally, we report that t he persistence of protein-DNA complexes induced by all three drugs was similar and, therefore, cannot account for differences in the potency of cytotoxicity of the aza-anthracenediones. Thus, we postulate that, while the total number of drug-induced protein-concealed DNA breaks i s an important indicator of drug toxicity, it is possible that the act ual nature of the breaks may differ among the aza-anthracenedione cong eners, and it is these differences in the actual proteins present in t he DNA breaks that differentiate between aza-anthracenediones.