Antagonistic effect of aclarubicin on camptothecin induced cytotoxicity: role of topoisomerase I.

The cellular target of camptothecin and several of its derivatives has been identified as topoisomerase I. Central to the cytotoxic action of camptothecin is the drug's ability to stimulate formation of topoisomerase I mediated DNA cleavages. Here we demonstrate that the intercalating antitumor agent aclarubicin inhibits camptothecin induced DNA single strand breaks in cells as measured by alkaline elution. When purified topoisomerase I was reacted with DNA, aclarubicin inhibited the formation of enzyme mediated DNA breaks induced by camptothecin. High aclarubicin concentrations (10 and 100 microM) caused a slight stimulation of topoisomerase I mediated DNA cleavage at a few distinct DNA sites. The cytotoxicity associated with camptothecin treatment measured in clonogenic assays was antagonized by preincubation with aclarubicin. This inhibitory effect of aclarubicin upon camptothecin action holds implications for the scheduling of aclarubicin in combination therapy with anticancer agents directed against topoisomerase I. Aclarubicin also inhibits the effect of topoisomerase II directed agents [such as etoposide (VP16), amsacrine (mAMSA), etc.] suggesting that aclarubicin acts against the two topoisomerases.