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Pyrimidine Metabolism in Human Leukocytes

I. Contribution of Exogenous Thymidine to DNA-Thymine and Its Effect on Thymine Nucleotide Synthesis in Leukemic Leukocytes¹

Medicine Branch and Laboratory of Physiology, National Cancer Institute, NIH, Bethesda, Maryland

The pathways for the formation of DNA-thymine from synthesis de novo and from exogenous thymidine (TdR) have been studied in intact leukocytes from patients with chronic myelogenous leukemia. The most significant observations were as follows: (a) DNA-thymine derived from exogenous TdR increases from 13% to 87% over a range of TdR concentrations from 0.03 µM to 300 µM. (b) TdR causes expansion of the total thymidine diphosphate and thymidine triphosphate (TTP) pool but does not influence the contribution of the pathway de novo to this pool. Thus, the increasing contribution of exogenous TdR to the formation of DNA-thymine occurs because of a progressive dilution of TTP synthesized de novo with TTP derived from exogenous TdR. (c) In concentrations greater than 0.3 µM, TdR inhibits DNA synthesis but not RNA synthesis. This inhibition is dependent on the continued presence of TdR in the medium and is reversed by the addition of deoxycytidine.

¹ Part of this work has been published in abstract form; see Cooper and Perry (13).

² Present address: II and IV (Harvard) Medical Service, Boston City Hospital, Boston, Mass.

³ To whom requests for reprints should be addressed at the Laboratory of Physiology, National Cancer Institute, NIH, Bethesda, Md.

Received 1/28/66. Accepted 5/24/66.