Molecular Pharmacology, Vol 17, 432-434, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Stimulation of Superoxide Formation by Actinomycin D and Its N²-Substituted Spin-Labeled Derivatives

¹ Laboratory of Environmental Biophysics, National Institute of Environmental Health Sciences, Post Office Box 12233, Research Triangle Park, North Carolina 27709

The mechanism of action of actinomycin D (AMD) is related to its interactions with DNA and inhibition of RNA synthesis. Recently, it has been shown that AMD stimulates the formation of superoxide when incubated with microsomal proteins. We have prepared N²-[4-(2,2,6,6-tetramethyl-1-piperidinyloxyl)]actinomycin D and the related 1,3-diaminopropane analogs, which were found to be more active than AMD in vivo against P-388 leukemia cells in spite of their poor DNA binding properties. We have investigated the stimulation of superoxide formation by these compounds as a possible mechanism of action. These analogs are more effective in stimulating O₂ uptake and the formation of O₂^- than the parent AMD. The better antitumor activities of these analogs may be related to the increased O₂ formation in vivo.

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ACKNOWLEDGMENTS The authors wish to thank Drs. C. F. Chignell and R. P. Mason for their helpful discussions during the preparation of the manuscript.