The Journal of Antibiotics
Online ISSN : 1881-1469
Print ISSN : 0021-8820
ISSN-L : 0021-8820
MECHANISM OF ACTION OF THE ANTHRACYCLINE ANTI-TUMOR ANTIBIOTICS, DOXORUBICIN, DAUNOMYCIN AND RUBIDAZONE: PREFERENTIAL INHIBITION OF DNA POLYMERASE α
GEORGE P. SARTIANOWILLIAM E. LYNCHW. DARRELL BULLINGTON
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1979 Volume 32 Issue 10 Pages 1038-1045

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Abstract

The effects of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone upon 3H-TTP incorporating activities of partially purified DNA polymerases and isolated liver nuclei were studied. Doxorubicin, daunomycin and rubidazone inhibited DNA polymerases α and β in proportion to drug dose, with consistent preferential inhibition of the α polymerase in comparison to the β polymerase for all three drugs. Studies with isolated nuclei, including normal liver nuclei (predominantly β polymerase activity), regenerating liver nuclei (α>β activity) and Brij 58, MgCl2-extracted regeneratingliver nuclei (predominantly α activity), showed inhibition in the order Brij 58, 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, daunomycin and rubidazone correlated with the degrees of inhibition of the polymerase activities, suggesting that intercalative binding is the mechanism by which these three agents inhibit the DNA polymerases. It is suggested that preferential inhibition of the α polymerase (the putative replicative polymerase) in comparison to the β polymerase (the presumed repair polymerase) may underlie the Cell Cycle Specific character of the mechanism of action of these anthracycline antibiotics.

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© Japan Antibiotics Research Association
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