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Role of Catabolism in Pyrimidine Utilization for Nucleic Acid Synthesis in Vivo¹

Departments of Biochemistry [G. M. C., S. G.], Medicine [W. F. D.], and Microbiology [S. G.], University of Miami, Coral Gables, Florida 33146, and Papanicolaou Cancer Research Institute [W. F. D.], Miami, Florida 33136

The incorporation of pyrimidines into nucleic acids in vivo is increased by inhibition of pyrimidine catabolism with diazouracil. The utilization of iodouracil or thymine for DNA synthesis can be increased approximately 20-fold by simultaneous administration of diazouracil and a purine deoxyribonucleoside. The incorporation of iodouracil and thymine, when administered at high doses, is elevated to nearly that obtained with the corresponding pyrimidine deoxyribonucleosides, while at low doses thymidine is utilized preferentially over thymine. Diazouracil and purine deoxyribonucleosides do not appreciably affect the incorporation of thymidine or iododeoxyuridine into DNA. The utilization of fluorouracil and uracil is also elevated by diazouracil but is not significantly affected by purine ribonucleosides. Diazouracil has a similar effect on pyrimidine incorporation in cells of the Dunning leukemia, rat liver, spleen, and small intestine, in spite of the differences in catabolic activity between these tissues, a finding that indicates the importance of systemic catabolism. The toxic and antitumor activities of fluorouracil are potentiated equally by diazouracil administration.

¹ This investigation was supported by Grant DRG-1076 from the Damon Runyon Memorial Foundation, and by Grant CA 12522 and Contract PH 43-64-80 from the National Cancer Institute, NIH.

² Predoctoral trainee supported by USPHS Training Grant HE-05463 from the National Heart and Lung Institute and a Robert E. Maytag Fellowship from the University of Miami.

Received 8/12/71. Accepted 11/ 3/71.