70 let methotrexátu v léčbě autoimunitních a nádorových onemocnění

English version

Autoři: M. Řiháček ^1,2; I. Řiháček ^1,3; L. Zdražilová-Dubská ^1,2,4; K. Pilátová ^1,2
Působiště autorů: Faculty of Medicine, Masaryk University, Kamenice, Brno, Czech RepublicHead prof. MUDr. J. Mayer, CSc. ¹; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech RepublicHead doc. MUDr. D. Valík, Ph. D. ²; Department of Pharmacology – ACIU, Faculty of Medicine, Masaryk University, Kamenice, Brno, Czech RepublicHead MUDr. R. Demlová, Ph. D. ⁴; nd Department of Internal Medicine, St. Anne’s University Hospital, Brno. Czech RepublicHead prof. MUDr. M. Souček, CSc. ³²
Vyšlo v časopise: Čes-slov Pediat 2014; 69 (3): 161-167.
Kategorie: Přehledový článek

Souhrn

Methotrexát byl před 70 lety zaveden do klinické praxe pro svou imunosupresivní a protinádorovou aktivitu. Přestože jsou neustále vyvíjena nová chemoterapeutika a imunomodulátory včetně antifolátových léčiv zůstává methotrexát zlatým standardem v terapii revmatoidní artritidy a některých maligních onemocnění. Methotrexát je dlouhodobě znám jako kompetitivní inhibitor enzymu dihydrofolátreduktasy, což je jeho hlavní mechanismus účinku. Byly popsány další farmakodynamické účinky a aktuálním předmětem zkoumání jsou mechanismy účinku nezávislé na inhibici tohoto enzymu. Při léčbě revmatoidní artritidy methotrexát snižuje hladiny významných mediátorů zánětu, jako jsou polyaminy a leukotrien-B4. Methotrexát snižuje expresi genů Jun N-terminální kinázy a B-cell lymfomu 2. Jeho endogenními metabolity jsou 7-hydroxymethotrexát, který vzniká jaterní biotransformací parentální sloučeniny a intracelulárně syntetizované polyglutamátové formy. Metabolity methotrexátu jsou farmakologicky aktivní a mají rozdílnou inhibiční aktivitu vůči dihydrofolátreduktase. V tomto přehledovém článku shrnujeme aktuální poznatky o léčivu v onkologické a revmatologické terapii a diskutujeme nové potenciální biomarkery toxicity, jejichž monitorování by mohlo zlepšit zavedené terapeutické protokoly.

Klíčová slova:
methotrexát, autoimunitní onemocnění, nádory, biologické markery, toxicita, nežádoucí účinky

Zdroje

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