Addition of leucovorin in modulation of 5‐fluorouracil with methotrexate: Potentiating or reversing effect?

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Abstract
Potentiation of the anti‐tumor activity of 5‐fluorouracil (5FU) by methotrexate (MTX) and leucovorin (LV) requires careful scheduling to achieve the most favorable interactions between these 3 drugs. In vitro the 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 superior 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 moderately increased levels of the 5FU metabolite FdUMP, while LV/5FU reduced the free FdUMP levels. MTX/LV/5FU had a dual effect and FdUMP levels gave no clear indication regarding the anti‐proliferative effect that could be expected. In vivo the time‐dependent potentiation of MTX on the 5FU anti‐tumor activity was confirmed for the treatment of HNX‐I4C‐bearing 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 mice, MTX/5FU was comparable to LV/5FU, but the triple combination of MTX/LV/5FU seemed to have a better anti‐tumor effect. However, the toxicity of the latter treatment was greater than that of LV/5FU. The data from both in vitro and in vivo experiments failed to support the addition of LV to MTX/5FU therapy, possibly due to a reversing effect of LV. © 1995 Wiley‐Liss. Inc.

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