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Pharmacology and Toxicology of a Seven-Day Infusion of 1-ß-D-Arabinofuranosylcytosine plus Uridine in Dogs¹

Departments of Neoplastic Diseases [L. P., T. O., A. A., M. S., J. F. H.], Surgery [M. S.], and Pathology [J. S.], Mount Sinai School of Medicine, New York, New York 10029

In vitro studies of certain lymphoid tumor cells show potentiation of 1-ß-D-arabinofuranosylcytosine (ara-C) effects by uridine because it elevates intracellular uridine triphosphate, resulting in increased ara-C triphosphate levels. Seven-day continuous i.v. infusions of uridine at 123 mg/kg/h (2.5 g/sq m/h) were studied in 5 male beagles. Steady state levels of uridine were reached within 4 to 6 h and ranged from 2 to 5 x 10^-4 M over the course of the infusion. Steady state uracil levels ranged from 4 to 10 x 10^-4 M. After the end of infusion, uridine and uracil levels fell with a half-life of approximately 15 and 18 min, respectively. Toxicity in 2 dogs treated at this dose was limited to minimal diarrhea and a transient rise of alkaline phosphatase to 2 to 3 times normal. No drug toxicity was evident at sacrifice on Days 7 or 72. Three dogs received a 7-day infusion of ara-C plus uridine followed approximately 4 weeks later by an infusion of ara-C alone (or the same drugs in the reverse sequence). Coinfusion of 2.5 or 5.0 mg/kg/day (50 or 100 mg/sq m/day) of ara-C had no significant effects on uridine plasma levels or postinfusion half-lives. Similarly, no consistent effect was seen of uridine on ara-C plasma levels. Uridine coinfusion with ara-C resulted in a definite potentiation of myelosuppression; at 5.0 mg/kg/day x 7 of ara-C white blood cell and platelet nadirs (x 10³/µl) were 0.8 and 15 as compared to 3.6 and 66, respectively, with ara-C alone. One-third of the dogs developed reversibly elevated transaminases with the combination treatment. The results show that a minimally toxic dose of uridine enhances bone marrow and probably hepatic toxicity of coadministered ara-C.

¹ Supported in part by USPHS Research Grant CA 15936-03, by the United Leukemia Fund, Inc., New York, NY, by the T. J. Martell Foundation for Leukemia and Cancer Research, New York, NY, and by the Chemotherapy Foundation Inc., New York, NY.

² To whom requests for reprints should be addressed at Department of Neoplastic Diseases, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029.

Received 12/11/84. Accepted 2/15/85.