The activity of a highly purified cytidine triphosphate synthetase from calf liver was shown to be inhibited by 3-deazauridine triphosphate, a major metabolite of 3-deazuridine (deaza-UR) in tumor cells. The inhibition is competitive with respect to uridine triphosphate, and the average Ki value, determined by Dixon and Lineweaver-Burk plots, is 5.3 × 10-6m. Neither deaza-UR nor deazauridine monophosphate inhibited the enzyme to a significant extent. The amination of uridine triphosphate to cytidine triphosphate in extracts of leukemia L1210 cells was also inhibited by deazauridine triphosphate. Coupled with the finding that the inhibition of the in vitro growth of leukemia L1210 cells by deaza-UR is reversed by cytidine and to a lesser extent by uridine and 2′-deoxycytidine, but not by thymidine or 2′-deoxyuridine, this observation suggests that deaza-UR exerts its growth-inhibitory activity by interfering with the activity of the cytidine triphosphate synthetase.

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Supported by Grants AM-13337, National Institute of Arthritis and Metabolic Diseases, and CA-12585, National Cancer Institute, NIH, USPHS.

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