PROOXIDANT PROPERTIES OF METHOTREXATE - EVALUATION AND PREVENTION BY AN ANTIOXIDANT DRUG

Polymorphonuclear neutrophils (PMNs) have the ability to liberate larg e amounts of reactive oxygen species like hydrogen peroxide. This free radicals release may have beneficial effect in chemotherapy but may a lso lead to cytotoxicity in case of prolongated inflammatory reaction. This in vitro study demonstrates that methotrexate (MTX), an anticanc er drug, increases the amount of hydrogen peroxide released by stimula ted PMNs in a dose-dependent manner with a maximum increase of 43.7% ( i.e. 22 mu M Of hydrogen peroxide) for 500 mu M 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 associatio n of MTX with mesna, an anti-oxidant drug, allowed to suppress the exc ess 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 limite toxic effects induced by free radicals.