Mechanism of the inhibition of calf thymus DNA polymerases alpha and beta by daunomycin and adriamycin

Abstract

The anthracycline antibiotics, daunomycin and adriamycin, strongly inhibited the reactions of both DNA polymerase alpha and beta from calf thymus by competing with the template primers, i.e., activated DNA or initiated deoxyhomopolymers. DNA polymerase alpha was more sensitive to both drugs than DNA polymerase beta with all the template-primers tested. With poly(dT).oligo(dA), the activity of the alpha-enzyme was extremely sensitive to these drugs (Ki, 0.9 microM for daunomycin), while that of the beta-enzyme was relatively resistant (Ki, 25 microM for daunomycin). Much stronger inhibition was produced by preincubating these drugs with the enzymes than with the template-primers, and the inhibition of DNA polymerase activity was reversed by the addition of excess template-primers. These results indicate that the inhibition was produced mainly by direct interaction of the drugs with DNA polymerases rather than by impairing the template activity of DNA due to intercalation of the drugs. Although adriamycin inhibited DNA polymerases alpha and beta to slightly higher extents than daunomycin, the modes of inhibition by these two drugs were quite similar.