Role of catabolism in pyrimidine utilization for nucleic acid synthesis in vivo.

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.