This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Klubes, P. Articles by Cerna, I. Search for Related Content PubMed PubMed Citation Articles by Klubes, P. Articles by Cerna, I.

Use of Uridine Rescue to Enhance the Antitumor Selectivity of 5-Fluorouracil¹

Department of Pharmacology, George Washington University Medical Center, Washington, D. C. 20037

We examined the ability of uridine to increase the therapeutic index of 5-fluorouracil (FUra) against C57BL/6 x DBA/2 F₁ mice bearing a Day 1 B16 melanoma or L1210 leukemia. FUra (400, 600, or 800 mg/kg, i.p.) followed in 24 hr by a 5-day s.c. infusion with uridine (5 g/kg/day, s.c.) was compared with the maximum tolerated dose of FUra (200 mg/kg, i.p.) plus a 5-day infusion with 0.9% NaCl solution. High-dose FUra plus delayed infusion with uridine was more effective than FUra (200 mg/kg) in inhibiting the growth of the B16 melanoma. High-dose FUra plus uridine rescue was, however, no more effective than FUra (200 mg/kg) in increasing the survival times of mice bearing the L1210 leukemia.

To see if uridine rescue from FUra toxicity correlated with effects against a sensitive normal tissue, bone marrow nucleated cellularity of normal, non-tumor-bearing mice was monitored after drug treatment. In mice treated with FUra (200 mg/kg) followed in 24 hr by a 5-day infusion with either uridine (5 g/kg/day) or 0.9% NaCl solution, there was not as great a decrease in cellularity at the nadir with uridine, and, in addition, uridine accelerated recovery as compared to 0.9% NaCl solution. Furthermore, uridine (5 g/kg/day), but not thymidine (dThd) (5 g/kg/day) or 2'-deoxyuridine (dUrd) (5 g/kg/day), had a sparing effect on the depression in bone marrow nucleated cellularity seen at the nadir on Day 4 after Fura (200 mg/kg).

The specificity of uridine to rescue mice from the lethal toxicity of the related fluorinated pyrimidines, 5-fluorouridine and 5-fluoro-2'-deoxyuridine, was also examined. Mice were treated with 5-fluorouridine (250 mg/kg, i.p.) followed in 24 hr by a 5-day infusion with uridine (1, 5, or 10 g/kg/day), dThd (1, 5, or 10 g/kg/day), or dUrd (1 or 5 g/kg/day). Uridine (1, 5, or 10 g/kg/day) rescued mice from the lethal toxicity of 5-fluorouridine, whereas dThd or dUrd was ineffective. Similarly, a 5-day infusion with uridine, but not dThd or dUrd, rescued mice from the lethal toxicity of 5-fluoro-2'-deoxyuridine (1800 mg/kg, i.p.).

¹ This investigation was supported by Grants CH-160 from the American Cancer Society and CA-17601 from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at the Department of Pharmacology, George Washington University Medical Center, 2300 Eye Street, N. W., Washington, D. C. 20037.

Received 10/20/82. Accepted 4/ 8/83.