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Methotrexate induced apoptotic and necrotic chromatin changes in rat myeloid leukemia cells

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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 18FDG 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.

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Acknowledgments

This work was supported by Hungarian Scientific Research Fund (OTKA grant) T42762 grant to G.B.

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Authors and Affiliations

  1. Department of Nuclear Medicine, University of Debrecen, Debrecen, Hungary

    Gyorgy Trencsenyi & Fruzsina Bako

  2. Department of Biotechnology and Microbiology, University of Debrecen, 1 Egyetem Square, Debrecen, 4010, Hungary

    Gabor Nagy & Gaspar Banfalvi

  3. Institute of Preventive Medicine, University of Debrecen, Debrecen, Hungary

    Pal Kertai

Authors
  1. Gyorgy Trencsenyi
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  2. Fruzsina Bako
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  3. Gabor Nagy
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  4. Pal Kertai
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  5. Gaspar Banfalvi
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Corresponding author

Correspondence to Gaspar Banfalvi.

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Responsible Editor: Liwu Li.

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Trencsenyi, G., Bako, F., Nagy, G. et al. Methotrexate induced apoptotic and necrotic chromatin changes in rat myeloid leukemia cells. Inflamm. Res. 64, 193–203 (2015). https://doi.org/10.1007/s00011-015-0797-x

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  • DOI: https://doi.org/10.1007/s00011-015-0797-x

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