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. Because dose intensification 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 conducted to determine the maximum dose of MTX tolerated after a priming dose of FU without leucovorin rescue, and to determine the toxicities of this combination. Subjects (n = 42) received a constant dose of FU followed in 2 hours by MTX; treatment was repeated every 3 weeks. Subjects initially received five doses of leucovorin (10 mg/m2 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 of subjects received escalating doses of MTX in a Fibonacci fashion. At the 1250 mg/m2 dose level, almost all previously untreated subjects tolerated the elimination of leucovorin rescue, without the occurrence of severe toxicity; this was 6 to 8 times the MTX dose that generally requires leucovorin rescue to avoid severe and lethal toxicity. The 24- and 48-hour MTX levels were at a level that usually requires leucovorin rescue. Previously treated subjects were less tolerant; 400 mg/m2 of MTX was the approximate maximum tolerated dose. Prior FU exposure appeared to protect tissues normally susceptible to MTX toxicity, and allowed safe administration of high dose MTX without leucovorin rescue.
White
R M
RM
Howard University Cancer Center, Washington, DC, USA.
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D008727:Methotrexate