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Alterations in Human Pyrimidine Metabolism as a Result of Therapy with 6-Azauridine^*

S. S. Cardoso, P. Calabresi and R. E. Handschumacher

( Departments of Pharmacology and Medicine, Yale University School of Medicine, New Haven, Connecticut)

Biochemical procedures are described which have been found useful in the study of normal pyrimidine metabolism as influenced by 6-azauridine. One technic involves the trapping of radioactive carbon dioxide liberated from orotic acid-7-C¹⁴ during the conversion of this compound to uridine nucleotides by isolated leukocytes in vitro. The susceptibility of this conversion to inhibition by azauridine 5'-phosphate derived metabolically from azauridine in vivo or in vitro has been measured.

The accumulation of orotic acid and orotidine by patients with leukemia treated with azauridine has been quantitated by ion-exchange analysis of the urine from these patients. Another indication of the effect of azauridine on the metabolism of orotic acid has been obtained by intravenous injection of a tracer dose of orotic acid-7-C¹⁴. Pre-treatment with azauridine of patients with neoplastic disease decreased the conversion of this pyrimidine to respiratory C¹⁴O₂ and uridine nucleotides and increased the urinary excretion of unchanged orotic acid.

^* Supported in part by grants (CY-2817, CY-5944 and OG-14) from the Public Health Service. Postdoctoral support for S.S.C. was provided by a Research Training Grant (CRTY-5012) from the National Cancer Institute, U.S. Public Health Service.

Present address: Department of Pharmacology, University of São Paulo Medical School, Ribeirão Preto, Brazil.

Scholar in Cancer Research of the American Cancer Society.

Received 6/24/61.

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