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Animal Models

The effects of dose, route of administration, drug scheduling and MDR-1 gene transfer on the genotoxicity of etoposide in bone marrow

Leukemia volume 14, pages 1796–1802 (2000)Cite this article

Abstract

We have used the bone marrow micronucleus assay (BMMN) as a measure of clastogenicity, in response to etoposide exposure in murine bone marrow. Oral delivery of etoposide resulted in a reduced number of micronucleated polychromatic erythrocytes (MPE) relative to the same dose delivered intraperitoneally (P < 0.001). Daily fractionation of the oral schedule of etoposide led to a more than six-fold increase in cumulative MPE frequency over that observed with the same total, unfractionated dose, with the potency of the response increasing with serial exposure (r = 0.79). Retrovirally-mediated expression of MDR1 in murine bone marrow resulted in partial protection against the clastogenic activity of etoposide relative to mock transduced control mice. The model system developed has indicated a variety of factors able to influence the genotoxicity of etoposide. It should now be possible to further exploit this model in order to define other factors governing haemopoietic sensitivity to etoposide.

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Acknowledgements

SDT is in receipt of an MRC studentship award and a Zeneca case award. Research undertaken in the Paterson Institute was supported by the Cancer Research Campaign (UK) and the NHS Research and Development Levy. CB is funded by the Deutsche Krebshilfe (10–1456 Ba2). We thank L Woolford, M Willington and T McNally for technical assistance and Prof OB Eden for his generous support and advice.

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Author notes

  1. H-G Eckert

    Present address: EUFETS GmbH, Idar-Oberstein, Vollmersbachstraße 66, 55743, Germany

Authors and Affiliations

  1. Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK

    SD Turner, JA Rafferty, LJ Fairbairn & LS Lashford

  2. Academic Unit of Paediatric Oncology, Christie Hospital (NHS Trust), Manchester, UK

    LS Lashford

  3. Central Toxicology Laboratory, AstraZeneca, Macclesfield, UK

    J Ashby & H Tinwell

  4. Heinrich-Pette Institute, Hamburg, Germany

    H-G Eckert & C Baum

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Turner, S., Rafferty, J., Fairbairn, L. et al. The effects of dose, route of administration, drug scheduling and MDR-1 gene transfer on the genotoxicity of etoposide in bone marrow. Leukemia 14, 1796–1802 (2000). https://doi.org/10.1038/sj.leu.2401810

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