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In Vivo Effect of Hydroxyurea on Orotic Acid Synthesis¹

The Department of Medicine, School of Medicine, and the Department of Pharmacology, Division of Basic Health Sciences, Emory University, Atlanta, Georgia

Hydroxyurea is thought to inhibit DNA synthesis but the site of inhibition has not been established. The urinary excretion of orotic acid was measured in 6 patients, 5 with acute leukemia and 1 with metastatic melanoma, receiving 6-azauridine which is known to inhibit orotidylic decarboxylase. The orotic aciduria observed in these patients was reversed by the addition of hydroxyurea, suggesting inhibition of de novo pyrimidine biosynthesis at a step prior to the formation of orotic acid. No clear-cut potentiation of a chemotherapeutic effect of this combination of drugs was observed.

¹ A preliminary report was made to the American Association for Cancer Research, Philadelphia, April 1965 (Proc. Am. Assoc. Cancer Res., 6: 67, 1965). This investigation was supported in part by USPHS Research Grants No. CA-05733-03, -04, and CA-03227-08, -09 from the National Cancer Institute and by Grant No. FR-39 from the Division of Research Facilities and Resources, NIH.

Received 1/10/66.