ACLACINOMYCIN-A STABILIZES TOPOISOMERASE-I COVALENT COMPLEXES

Aclacinomycin A (aclarubicin) is an anthracycline anticancer agent wit h demonstrated activity against both leukemias and solid tumors, Previ ous results suggested that a major activity of aclacinomycin A is the inhibition of topoisomerase II catalytic activity, We have applied a y east system to test whether aclacinomycin A is a topoisomerase II inhi bitor in vivo and to test whether we could identify other important ta rgets of this drug, We have found that overexpression of yeast topoiso merase II confers resistance to aclacinomycin A in yeast, consistent w ith the hypothesis that this drug is a catalytic inhibitor of topoisom erase II, Interestingly, we have also found that in yeast, aclacinomyc in A, like camptothecin, stabilizes topoisomerase I cleavage, We carri ed out biochemical analysis with purified human topoisomerase I and de monstrated that this drug efficiently stabilizes topoisomerase I coval ent complexes, indicating that aclacinomycin A represents a novel clas s of combined topoisomerase I/II inhibitor.