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Inhibition of Ribonucleotide Reductase by Gallium in Murine Leukemic L1210 Cells¹

Division of Cancer and Blood Diseases, Department of Medicine [C. R. C., J. N.], and Departments of Ophthalmology and Microbiology [J. G., W. J. O.], Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Our previous studies of the mechanism of cell growth inhibition by gallium have suggested that the block in cellular iron uptake induced by transferrin-gallium results in an inhibition of the iron-dependent M2 subunit of ribonucleotide reductase. However, it is not known whether the inhibitory effect of gallium on ribonucleotide reductase is solely the result of limiting iron availability for enzyme activity or whether a direct effect of intracellular gallium on the enzyme is also involved. In the present study, utilizing a cell-free assay, we show that gallium nitrate directly inhibits CDP and ADP reductase activity. Inhibition of DNA synthesis by gallium nitrate thus appears to be due to a combination of a block in iron availability to ribonucleotide reductase and a direct inhibition of the enzyme by gallium.

¹ This work was supported by USPHS Grants R01 CA41740 (C. R. C.) and NEI P30-EY01931 (W. J. O.).

² To whom requests for reprints should be addressed, at Division of Cancer and Blood Diseases, Medical College of Wisconsin, 8700 W. Wisconsin Ave., Milwaukee, WI 53226.

³ Present address: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI.

Received 9/10/91. Accepted 9/27/91.

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