Mechanism of action of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone: Preferential inhibition of DNA polymerase .ALPHA..

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Abstract
The effects of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone upon 3H-TTP [thymidine triphosphate] incorporating activities of partially purified DNA polymerases and isolated liver nuclei were studied. Doxorubicin, daunomycin and rubidazone inhibited DNA polymerases .alpha. and .beta. in proportion to drug dose, with consistent preferential inhibition of the .alpha. polymerase in comparison to the .beta. polymerase for all 3 drugs. Studies with isolated nuclei, including normal liver nuclei (predominantly .beta. polymerase activity), regenerating liver nuclei (.alpha. > .beta. activity) and Brij 58 MgCl2-extracted regenerating liver nuclei (predominantly .alpha. activity), showed inhibition in the order Brij MgCl2-extracted regenerating > regenerating > normal nuclei, corroborating the results obtained with the separate polymerase activities. The elevations in DNA melting temperatures caused by the binding of doxorubicin, duanomycin and rubidazone correlated with the degrees of inhibition of the polymerase activities, suggesting that intercalative binding is the mechanism by which these 3 agents inhibit the DNA polymerases. Preferential inhibition of the .alpha. polymerase (the putative replicative polymerase) in comparison to the .beta. polymerase (the presumed repair polymerase) may underlie the cell cycle specific character of the mechanism of action of these anthracycline antibiotics.