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Studies on the Effects of Hydroxyurea and Other Anticancer Drugs upon Pyrimidine Metabolism¹

Department of Medicine (Division of Hematology), School of Medicine, and Departments of Pharmacology and Biochemistry, Division of Basic Health Sciences, Emory University, Atlanta, Georgia 30322

The reversal of azauridine-induced oroticaciduria by hydroxyurea has been studied to further elucidate the control mechanisms involved in the de novo pathways of pyrimidine biosynthesis. No direct effect of hydroxyurea upon partially purified aspartate transcarbamylase and dihydroorotase was observed. Hydroxyurea selectively inhibited the incorporation of ¹⁴C-labeled aspartate, orotate, and formate into the DNA bases of human leukemic cells incubated in vitro. No effect of hydroxyurea was observed in the RNA bases isolated from these leukemic cells. Other chemotherapeutic agents, including 5-iododeoxyuridine, 5-fluorodeoxyuridine, Methotrexate, cytosine arabinoside, and cyclophosphamide, were administered to patients receiving 6-azauridine. Only Methotrexate and cyclophosphamide inhibited orotic acid excretion in a manner similar to hydroxyurea. These results suggest that the control of pyrimidine biosynthesis is linked to DNA synthesis or function in an as yet unexplained manner.

¹ This investigation was supported by USPHS Research Grants CA-05733 and CA-03528 from the National Cancer Institute and FR-39 from the General Clinical Research Centers Branch, Division of Research Facilities and Resources.

² Present Address: Department of Medicine, Albert Einstein School of Medicine, New York, New York.

Received 8/12/68. Accepted 2/13/69.