Melphalan reduces the severity of experimental colitis in mice by blocking tumor necrosis factor-alpha signaling pathway.
Melphalan is an alkylating agent, which is commonly used as an antineoplastic drug. Its cytostatic effect can be realized in humans in the dose range of 0.6-1.4 mg/kg body weight. However, previously it was shown that in the case of gradual dose decrease, the number of targets for alkylation was also reduced and the drug lost its cytostatic properties switching to cell growth modifier. It has been postulated that application of alkylating agents in such ultra-low concentrations (50- to 100-fold lower than cytostatic ones) may result in a beneficial effect in the therapy of diseases associated with mucosa inflammation. The aim of the article was to investigate the effect of ultra-low doses of melphalan in the murine experimental colitis induced by the replacement of drinking water with 5% solution of dextran sulphate sodium (DSS). Daily administration of melphalan (25 microg/kg body weight) markedly reduced the severity of DSS-colitis as determined by clinical and quantitative histological criteria. Both systemic and local anti-inflammatory effects of melphalan have been observed. The possible mechanisms of the beneficial effect of the drug have been discussed.
Shmarina
Galina
G
Research Centre for Medical Genetics, 1 Moskvorechie Street, Moscow 115478, Russia. osugariver@med-gen.ru
Pukhalsky
Alexander
A
Alioshkin
Vladimir
V
Sabelnikov
Alex
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002470:Cell Survival; D003092:Colitis / Q000188:drug therapy*; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D008558:Melphalan