ADDITION OF LEUCOVORIN IN MODULATION OF 5-FLUOROURACIL WITH METHOTREXATE - POTENTIATING OR REVERSING EFFECT

Potentiation of the anti-tumor activity of 5-fluorouracil (5FU) by met hotrexate (MTX) and leucovorin (LV) requires careful scheduling to ach ieve the most favorable interactions between these 3 drugs. In vitro t he triple combination of MTX/5FU/LV was tested at 4 time intervals and with 3 MTX concentrations in 3 cell lines. MTX/5FU/LV was never super ior to both 5FU/LV and MTX/5FU, moreover LV reduced growth inhibition by MTX/5FU in 2 cell lines. MTX/5FU was associated with only moderatel y increased levels of the 5FU metabolite FdUMP, while LV/5FU reduced t he free FdUMP levels. MTX/LV/5FU had a dual effect and FdUMP levels ga ve no clear indication regarding the anti-proliferative effect that co uld be expected. In vivo the time-dependent potentiation of MTX on the 5FU anti-tumor activity was confirmed for the treatment of HNX-14C-be aring mice. Addition of LV to the MTX/5FU combination failed to cause a gain in anti-tumor efficacy. For the treatment of Colon-26-bearing m ice, MTX/5FU was comparable to LVI 5FU, but the triple combination of MTX/LV/5FU seemed to have a better anti-tumor effect. However, the tox icity of the latter treatment was greater than that of LV/5FU. The dat a from both in vitro and in vivo experiments failed to support the add ition of LV to MTX/5FU therapy, possibly due to a reversing effect of LV. (C) 1995 Wiley-Liss, Inc.