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Inhibition of Rat Liver DNA Polymerase by Nitrosoureas and Isocyanates¹

The Worcester Foundation for Experimental Biology, Inc., Shrewsbury, Massachusetts 01545 [B. B. B., E. F. B.]; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710 [J. L.]; and Southern Research Institute, Birmingham, Alabama 35205 [G. P. W.]

The effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea on two non-mitochondrial DNA polymerases (I and II) purified from rat liver and hepatoma were examined. The activity of DNA polymerase I was not altered by treatment with any of the nitrosoureas or the corresponding isocyanates, 2-chloroethyl isocyanate and cyclohexyl isocyanate. Incubation of DNA polymerase II with the nitrosoureas (1 mM) inhibited its enzymatic activity 30 to 45%. DNA polymerase II was inhibited 75 and 90% by 1 mM 2-chloroethyl isocyanate and cyclohexyl isocyanate, respectively.

The nitrosoureas appear to exert their inhibitory action on the enzyme (DNA polymerase II) rather than on the DNA template. Pretreatment of the enzyme increased the degree of inhibition by 1 mM nitrosourea (50 to 60% inhibition) or 2-chloroethyl isocyanate (>90% inhibition), whereas pretreatment of the DNA template did not enhance the inhibitory effect.

The three nitrosoureas are equally effective as inhibitors of DNA polymerase II. 2-Chloroethyl isocyanate and cyclohexyl isocyanate are better inhibitors than are the nitrosoureas. Since further decomposition products of the isocyanates, 2-chloroethylamine and cyclohexylamine, do not inhibit DNA polymerase II, we conclude that the isocyanates, which are decomposition products of the nitrosoureas, are the active inhibitors of the enzyme.

¹ This investigation was supported by USPHS Grants CA12708, CA15360-01, CA08800, and CA11265 from the National Cancer Institute.

Received 5/ 9/74. Accepted 8/30/74.

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