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Further Studies on the Mechanism of Action of Hydroxyurea¹

Departments of Medicine and Biochemistry, University of Minnesota Medical Center, Minneapolis, Minnesota 55455

Addition of the four deoxyribonucleosides in vitro to 6C3HED mouse ascites tumor stimulates ³²P incorporation into DNA and depresses incorporation into RNA at concentrations greater than 10^-4 M. The four ribonucleosides stimulate incorporation into both DNA and RNA. Hydroxyurea blocks the ribonucleoside stimulation of ³²P incorporation into DNA but not RNA. The inhibition of ³²P incorporation into DNA by hydroxyurea is not prevented by the four deoxyribonucleosides in vitro when added either initially or at intervals throughout the period of incubation. Studies in vivo also indicate the failure of deoxyribonucleosides to prevent inhibition induced by hydroxyurea. The failure of deoxyribonucleosides to prevent the hydroxyurea effect cannot be explained on the basis of the failure of the added nucleosides to be incorporated into DNA or on the basis of their conversion to ribonucleosides and secondary inhibition of DNA synthesis. It would appear, on the basis of these data, that in this system the primary site of action of hydroxyurea is not at the level of conversion of ribonucleotides to deoxyribonucleotides and, therefore, additional sites of action should be investigated.

¹ This investigation was supported in part by USPHS Research Grants CA-08344, CA-08832, CA-05862, CA-05158, and CA-08101 from the National Cancer Institute.

Received 9/20/67. Accepted 2/18/68.

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