title: Methotrexate induced apoptotic and necrotic chromatin changes in rat myeloid leukemia cells.
abstract: OBJECTIVE
  It was tested as to why low-dose methotrexate (MTX) effective against rheumatoid arthritis poses considerable health risk at higher doses.
  
  
  METHODS
  The tumorigenic potential of My1/De blast cells was followed by cytology and by the kinetics of (18)FDG uptake. The toxicity of MTX on chromatin condensation was compared to predictive normal intermediates of chromosome condensation in control cells.
  
  
  RESULTS
  MTX below 0.1 µg/ml did not cause visible changes in interphase chromatin structure. At its lowest toxic concentration (0.1 µg/ml) chromatin margination was confined to the outer edge of the nucleus. Between 0.1 and 5 µg/ml concentrations apoptotic chromatin shrinkage correlated with the dose of MTX. Apoptosis was exerted in early S phase excluding the mitotic effect. At higher MTX concentrations (>10 µg/ml) necrotic disruption and expansion took place. The lowest necrotic concentration (10 µg/ml) was close to highest apoptotic MTX concentration (5 µg/ml).
  
  
  CONCLUSIONS
  The switch from apoptosis to inflammatory necrosis taking place within a narrow concentration range supports the notion of a narrow therapeutic spectrum. Chromatin changes are early markers of genotoxicity at much lower concentrations than citogenetic changes in properly chosen sensitive cells.
authors: Department of Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors: Gyorgy
authors: G
authors: Trencsenyi
authors: Fruzsina
authors: F
authors: Bako
authors: Gabor
authors: G
authors: Nagy
authors: Pal
authors: P
authors: Kertai
authors: Gaspar
authors: G
authors: Banfalvi
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D042003:DNA Packaging / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D000964:Antimetabolites, Antineoplastic; D002843:Chromatin; D015127:9,10-Dimethyl-1,2-benzanthracene; D008727:Methotrexate