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 o f camptothecin is the drug's ability to stimulate formation of topoiso merase I mediated DNA cleavages. Here we demonstrate that the intercal ating antitumor agent aclarubicin inhibits camptothecin induced DNA si ngle strand breaks in cells as measured by alkaline elution. When puri fied topoisomerase I was reacted with DNA, aclarubicin inhibited the f ormation of enzyme mediated DNA breaks induced by camptothecin. High a clarubicin concentrations (10 and 100 mu M) caused a slight stimulatio n 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. T his inhibitory effect of aclarubicin upon camptothecin action holds im plications for the scheduling of aclarubicin in combination therapy wi th anticancer agents directed against topoisomerase I. Aclarubicin als o inhibits the effect of topoisomerase II directed agents [such as eto poside (VP16), amsacrine (mAMSA), etc.] suggesting that aclarubicin ac ts against the two topoisomerases.