Cl. Vanderwilt et al., ADDITION OF LEUCOVORIN IN MODULATION OF 5-FLUOROURACIL WITH METHOTREXATE - POTENTIATING OR REVERSING EFFECT, International journal of cancer, 61(5), 1995, pp. 672-678
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.