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Hydroxyurea-induced Inhibition of Deoxyribonucleotide Synthesis: Studies in Intact Cells¹

Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, New York 10021, and Mount Desert Island Biological Laboratory, Salisbury Cove, Maine

Hydroxyurea-induced inhibition of thymidine incorporation by monolayers of HeLa cells was partially prevented and reversed by addition of deoxyadenosine, deoxyguanosine, and deoxycytidine to the culture medium. All 3 deoxyribonucleosides were required for optimal effect. Hydroxyurea inhibited incorporation of thymidine into DNA of embryos of the sand-dollar species Echinarachnius parma. The onset of inhibition was delayed for 3–4 synthesis (S) periods when the drug was added at fertilization, but was evident with the next replication cycle following drug addition between the 5th and 6th S period. Hydroxyurea did not alter rates of leucine incorporation into protein regardless of the time of drug exposure. Echinoderm ova possess significant quantities of preformed deoxyribonucleotides; previous studies with 5-fluorodeoxyuridine have suggested that these stores can supply the embryo with the thymidylate required for DNA replication over 6 S periods following fertilization.

These observations, i.e., partial reversal of drug-induced inhibition by exogenous deoxyribonucleosides in HeLa cells, and the insensitivity of sand-dollar embryos to hydroxyurea during initial S periods, are compatible with the postulate that this compound inhibits reduction of ribonucleotides to deoxyribonucleotides.

¹ This investigation was supported in part by NCI Grants CA-07860 and CA-08748, and by American Cancer Society Grant ACS-T40. A preliminary report on some phases of this work has been presented (31).

Received 7/ 1/66. Accepted 10/24/66.

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