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Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite

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Abstract

Background: The ifosfamide metabolite chloroacetaldehyde had been made responsible for side effects only. We found in previous studies a strong cytotoxicity on human MX-1 tumor cells and xenografts in nude mice. Chloroacetaldehyde is supposed to act via alkylation or by inhibition of mitochondrial oxidative phosphorylation with decrease of ATP. The aim of this study was to further elucidate chloroacetaldehyde’s mode of action. Methods: MX-1 breast carcinoma cells were measured for ATP-content after exposure to chloroacetaldehyde. Further, the effect of chloroacetaldehyde on DNA-synthesis and its potency of causing strand-breaks or cross-links were investigated by bromodeoxyuridine-incorporation, comet-assay and a DNA interstrand cross-linking-assay. Results: Chloroacetaldehyde in high concentrations induces a reduction of ATP-levels when anaerobic glycolysis is blocked by oxamate and reduces the bromodeoxyuridine-incorporation to 46.3% after 4 h when used in IC50 concentrations (7.49 μmol/l). In addition we observed DNA single strand-breaks in MX-1 cells treated with chloroacetaldehyde visible in the Comet assay, but no DNA-cross-linking by comet assay and cross-linking assay. Conclusion: In summary, our results show that chloroacetaldehyde influences the oxidative phosphorylation in mitochondria, however, this is observed only in high concentrations and is not of clinical relevance because the tumor cells regenerate ATP by anaerobic glycolysis. Nevertheless, chloroacetaldehyde causes DNA-strand-breaks and strong inhibition of DNA-synthesis.

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Abbreviations

BrdU:

Bromodeoxyuridine

ELISA:

Enzyme-linked immuno sorbent assay

IC50 :

Inhibitor concentration 50

MMS:

Methylmethanosulfonate

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

PBS:

Phosphate-buffered saline

Tris:

2-Amino-2-(hydroxymethyl)-propan-1,3-diol

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Acknowledgements and conflict of interest statement

We thank Heike Bahrs and Monica Vollmert for their skillful technical assistance. None of the authors has a conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Section of Hematology/Oncology, University of Luebeck, 23538, Luebeck, Germany

    Svenja K. Brüggemann, Kerstin Radike, Kirsten Braasch, Jürgen Hinrichs, Jens Kisro, Wibke Hagenah, Stefan O. Peters & Thomas Wagner

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  1. Svenja K. Brüggemann
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  2. Kerstin Radike
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  3. Kirsten Braasch
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  4. Jürgen Hinrichs
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  7. Stefan O. Peters
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  8. Thomas Wagner
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Correspondence to Thomas Wagner.

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Brüggemann, S.K., Radike, K., Braasch, K. et al. Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite. Cancer Chemother Pharmacol 57, 349–356 (2006). https://doi.org/10.1007/s00280-005-0061-0

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  • DOI: https://doi.org/10.1007/s00280-005-0061-0

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