Nové možnosti starého léku: DHFR- a non-DHFR-mediované účinky metotrexátu na nádorové buňky

Metotrexát, strukturální analog kyseliny listové, je jedním z nejčastěji používaných chemoterapeutik především pro léčbu hematoonkologických onemocnění, solidních nádorů, ale také některých autoimunitních poruch. Primárně metotrexát narušuje folátový metabolizmus inhibicí dihydrofolátreduktázy, což má za následek potlačení syntézy pyrimidinových a purinových prekurzorů. Nedostatek stavebních kamenů nukleových kyselin se pak odráží v cytostatickém, cytotoxickém a diferenciačním efektu metotrexátu. Mezi další procesy, které jsou ovlivněny inhibicí folátového metabolizmu, patří metylace biomolekul, především proteinů a DNA. Metotrexát však působí na metabolické dráhy a buněčné procesy i nezávisle na metabolizmu folátů. Na základě podobnosti struktury metotrexátu a funkčních skupin některých inhibitorů histondeacetyláz bylo predikováno a poté i experimentálně potvrzeno, že metotrexát má schopnost inhibovat histondeacetylázy. Dále byla prokázána schopnost metotrexátu účinně ovlivňovat glyoxalázový a antioxidační systém. I když je metotrexát používán jako folátový antagonista v protinádorové terapii více než 60 let, odhalování jeho dalších cílů působení na molekulární i buněčné úrovni stále pokračuje.

Klíčová slova:
metotrexát – folátový metabolizmus – dihydrofolátreduktáza – metylace – inhibitory histondeacetylázy – glyoxalázový systém – oxidativní stres

Autoři: J. Neradil ^1,2; G. Pavlasova ¹; R. Veselska ^1,3
Působiště autorů: Laboratory of Tumor Biology, Department of Experimental Biology, School of Science, Masaryk University, Brno, Czech Republic ¹; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic ²; Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Brno, Czech Republic ³
Vyšlo v časopise: Klin Onkol 2012; 25(Supplementum 2): 87-92

Práce byla podpořena Evropským fondem pro regionální rozvoj a státním rozpočtem České republiky (OP VaVpI – RECAMO, CZ.1.05/2.1.00/03.0101) a interním projektem Masarykovy univerzity MUNI/C/0803/2011.

Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů.

Obdrženo: 1. 10. 2012
Přijato: 6. 11. 2012

Souhrn

Klíčová slova:
metotrexát – folátový metabolizmus – dihydrofolátreduktáza – metylace – inhibitory histondeacetylázy – glyoxalázový systém – oxidativní stres

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