Pro-oxidant properties of methotrexate: evaluation and prevention by an anti-oxidant drug.
Polymorphonuclear neutrophils (PMNs) have the ability to liberate large amounts of reactive oxygen species like hydrogen peroxide. This free radicals release may have beneficial effect in chemotherapy but may also lead to cytotoxicity in case of prolongated inflammatory reaction. This in vitro study demonstrates that methotrexate (MTX), an anticancer drug, increases the amount of hydrogen peroxide released by stimulated PMNs in a dose-dependent manner with a maximum increase of 43.7% (i.e. 22 microM of hydrogen peroxide) for 500 microM of MTX. The mechanism which govern MTX reaction seems to be a result of an intracellular pro-oxidant mechanism by intervention on the oxidative metabolism of PMNs rather than a cell-free chemical interaction. Moreover, an association of MTX with mesna, an anti-oxidant drug, allowed to suppress the excess of hydrogen peroxide production. This association might be used in anticancer therapy, during oxidative burst, particularly when MTX is used in high concentrations, in order to limit toxic effects induced by free radicals.
Faculté de Pharmacie, Laboratoire de Pharmacologie, Pharmacocinétique et Pharmacie Clinique, Lille, France.
B
B
Gressier
S
S
Lebegue
C
C
Brunet
M
M
Luyckx
T
T
Dine
M
M
Cazin
J C
JC
Cazin
D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D016166:Free Radical Scavengers; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D015080:Mesna / Q000494:pharmacology*; D008727:Methotrexate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*
D000975:Antioxidants; D016166:Free Radical Scavengers; D016877:Oxidants; D006861:Hydrogen Peroxide; D015080:Mesna; D008727:Methotrexate