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Molecular Pharmacology, Vol 2, 248-258, Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of the Biosynthesis of Thymidylic Acid by 4-N-Hydroxy-2'-Deoxycytidine in L5178Y Leukemic Cells

D. J. NELSON 1 and C. E. CARTER 1

1 Department of Pharmacology, Western Reserve University School of Medicine, Cleveland, Ohio, and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut

Reproduction of L5178Y leukemic cells in culture was inhibited by 10-5M 4-N-hydroxy-2'-deoxycytidine. Thymidine and deoxyuridine specifically protected the cells from growth inhibition. In whole cell incubations in vitro thymidine-3H incorporation into DNA-thymine was slightly stimulated, whereas deoxycytidine-3H, deoxyuridine-3H, and formate-14C incorporation into acid-soluble thymidylate nucleotides and DNA-thymine was markedly inhibited by 4-N-hydroxy-2'-deoxycytidine. Thymidylate synthetase activity from partially purified extracts of E. coli and cell-free preparations of sonically disrupted L5178Y leukemic cells was competitively inhibited by 4-N-hydroxy-2'-deoxycytidylic acid.

Studies in which L5178Y leukemic cells were incubated in vitro with 4-N-hydroxy-2'-deoxycytidine-3H demonstrated that the analog was phosphorylated to the monophosphate. Although 4-N-hydroxy-2'-deoxycytidine did not inhibit phosphorylation of thymidine-3H, deoxyuridine-3H, or deoxycytidine-3H in vitro, the phosphorylation of 4-N-hydroxy-2'-deoxycytidine-3H in this system was inhibited by thymidine and deoxyuridine. These experiments indicate that 4-N-hydroxy-2'-deoxycytidine is a functional analog of deoxyuridine that is phosphorylated to 4-N-hydroxy-2'-deoxycytidylic acid, and produces its cellular effects through inhibition of the biosynthesis of thymidylic acid.

Note:
ACKNOWLEDGMENTS We are grateful to Dr. G. A. Fischer for his help with L5178Y growth experiments and to Miss Judith Pascale and Dr. William H. Darrow for their excellent technical assistance. This research was supported by Grant No. CA 08236 from the United States Public Health Service.

Submitted on February 7, 1966




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