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Inhibition of Ribonucleoside Diphosphate Reductase by Hydroxyurea¹

Department of Chemistry II, Karolinska Institutet, Stockholm, Sweden

Hydroxyurea, a compound which inhibits the growth of rapidly proliferating tissues in animals and man, is known to inhibit DNA synthesis, and studies in crude systems have indicated that it does so by preventing the reduction of ribonucleotides to deoxyribonucleotides.

This study demonstrates hydroxyurea-induced inhibition of the reduction of ribonucleotides by a highly purified enzyme system from Escherichia coli B. The inhibition (70% at 3 x 10^-3 M under standard incubation conditions) is dependent on the concentration of hydroxyurea and on the duration of exposure of the enzyme to hydroxyurea. The effect of hydroxyurea is specific for protein B2 of the ribonucleoside diphosphate reductase system. The inhibition of enzymatic activity is apparently irreversible, although there is negligible irreversible binding of ¹⁴C-labeled hydroxyurea to the enzyme protein.

¹ This investigation was supported in part by Grant No. 67:52 from the Swedish Cancer Society, No. 470 from the Damon Runyon Fund, and CA 07897-04 from the NIH to Peter Reichard.

² Leave of absence from the Sloan-Kettering Institute for Cancer Research, New York, New York during the tenure of an Alfred P. Sloan Award in Cancer Research, August 1966 to July 1967.

³ Address reprint requests to Dr. Irwin H. Krakoff, Sloan-Kettering Institute, 410 East 68th Street, New York, New York 10021.

⁴ Special Postdoctoral Fellow of the National Institute of General Medical Science, USPHS (Grant No. 1-F3-GM-32, 309-01).

Received 11/16/67. Accepted 4/13/68.

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