title: Addition of leucovorin in modulation of 5-fluorouracil with methotrexate: potentiating or reversing effect?
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-14C-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.
authors.affiliation: Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: C L
authors.initials: CL
authors.lastname: Van der Wilt
authors.forename: B J
authors.initials: BJ
authors.lastname: Braakhuis
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: M
authors.initials: M
authors.lastname: De Jong
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005260:Female; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
chemical_list: D005468:Fluorodeoxyuridylate; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate