5-FLUOROURACIL MODULATES THE TOXICITY OF HIGH-DOSE METHOTREXATE

Pretreatment with 5-fluorouracil (FU) attenuated the toxicity of high dose methotrexate (MTX) in in vitro and in vivo models. BecuUSe dose i ntensification of the MTX reversed the fluoropyrimidine antagonism of MTX activity in these models, administering FU before the MTX offered the potential advantage of MTX dose intensity and low toxicity without the confounding effects of leucovorin rescue. The current study was c onducted to determine the maximum dose of MTX tolerated after a primin g dose of FU without leucovorin rescue, and to determine the toxicitie s of this combination, Subjects (n = 42) received a constant dose of F U followed in 2 hours by MTX; treatment was repeated every 3 weeks. Su bjects initially received five doses of leucovorin (10 mg/m(2) every 6 hours); this was reduced to two doses, then to zero doses (no rescue) if less than grade 2 toxicity occurred in prior treatments. Cohorts o f subjects received escalating doses of MTX in a Fibonacci fashion. At the 1250 mg/m(2) dose level, almost all previously untreated subjects tolerated the elimination of leucovorin rescue, without the occurrenc e of severe toxicity; this was 6 to 8 rimes the MTX dose that generall y requires leucovorin rescue to avoid severe and lethal toxicity. The 24- and 48-hour MTX levels were at a level that usually requires leuco vorin rescue. Previously treated subjects were less tolerant; 400 mg/m (2) of MTX was the approximate maximum tolerated dose. Prior FU exposu re appeared to protect tissues normally susceptible to MTX toxicity, a nd allowed safe administration of high dose MTX without leucovorin res cue.