Potentiation of 5-fluorouracil induced inhibition of thymidylate synthase in human colon tumors by leucovorin is dose dependent.

Abstract

The schedule and dose dependency of leucovorin (LV) administration in order to potentiate the antitumor activity of 5-fluorouracil (5FU) is still a unclear issue.1,2,3 Traditionally two schedules for single agent of 5FU were used; weekly administration at 500 mg/m2 and daily (x 5) administration at 300-500 mg/m2, which was repeated every 4 weeks. These two schedules of 5FU have been combined with a variety of LV schedules, which can roughly be divided in high dose (2 hr infusion of LV at 500 mg/m2 with 5FU injected mid-infusion),4 intermediate dose (2 hr infusion of LV at 200 mg/m2)5,6 and low-dose LV (bolus injection of LV at 20-25 mg/m2 injected just before 5FU).6,7 LV has also been administered at similar doses but in different schedules. The response rates at the high and intermediate doses was almost always higher (about 30%) than for single agent 5FU, but for the low dose (as well as for oral LV) a larger variation in response rates was observed.6,7 At a recent symposium on modulation of 5FU8 a concensus was achieved that exposure to LV should be 2 hrs or longer in order to facilitate accumulation of polyglutamates of the reduced folate cofactor. The dose of LV remains un unresolved issue, although it was clear from preclinical studies that at least a concentration of 1 μM should be present in the culture medium in order to achieve modulation of 5FU.9 Although both the intermediate and the high dose of LV result in plasma concentrations of /-LV above this levels10 this does not provide information on the intra-tumoral concentration of LV and the reduced folate cofactor 5,10-methylene-tetrahydrofolate (CH2-THF).KeywordsIntermediate DoseHuman Colon TumorIntratumoral ConcentrationUnclear IssueCatalytic AssayThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.