High-dose 5-fluorouracil with delayed uridine "rescue" in mice

Because of the association between the incorporation of 5-fluorouracil (FUra) into RNA and cytotoxicity, uridine was examined for potential selective reduction of host toxicity. Male BALB/c x DBA/2 F1 mice (tumor free or bearing advanced colon tumor 26) were used. Two uridine schedules (each beginning 2 hr after FUra) have been successful: (a) uridine at 800 mg/kg every 2 hr for three doses followed 18 hr later by uridine at 800 mg/kg every 2 hr for four doses; or (b) two doses of uridine at 3500 mg/kg separated by an 18-hr interval. With two doses of uridine at 3500 mg/kg, the 50% lethal dose for a single dose of FUra in tumor-free mice was increased 68% from 190 to 320 mg/kg. White blood cell levels were depressed 67% after a single dose of FUra at 200 mg/kg, whereas white blood cells were depressed by only 39% when the same dose of FUra was followed by uridine rescue. In tumor-bearing mice, uridine rescue reduced FUra-induced host toxicity without significant loss of antitumor activity. Even more striking results were obtained with a combination containing N-(phosphonacetyl)-L-aspartate (200 mg/kg) and 6-methylmercaptopurine riboside (25 mg/kg), administered 24 hr before FUra. In this drug combination, the maximum tolerated dose of FUra is 40 mg/kg on a weekly schedule. With uridine rescue, FUra can be doubled to 80 mg/kg without increasing toxicity, resulting in significantly improved antitumor activity. Examination of the effect of uridine rescue on the incorporation of FUra into RNA and the subsequent recovery from inhibition of DNA synthesis in bone marrow versus tumor revealed that the uridine rescue schedule resulted in relatively faster clearance of FUra from RNA of both tissues but a striking enhancement of the rate of recovery of DNA synthesis only in the bone marrow.