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Enhancement of anthracycline and alkylator cytotoxicity by ethacrynic acid in primary cultures of human tissues

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Summary

Ethacrynic acid [2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxyl] acetic acid, is a water-soluble diuretic agent that has been shown to potentiate the in vitro cytotoxicity of chemotherapeutic agents in established cell lines. We used the differential staining cytotoxicity (DiSC) assay to determine whether ethacrynic acid at 1 and 3.3 µM would potentiate the cytotoxicity of nitrogen mustard and/or doxorubicin in primary cultures of hematologic neoplasms from heavily pretreated patients and in normal peripheral blood lymphocytes. At 3.3 µM, ethacrynic acid was toxic to 8 of 24 (33%) tumor specimens studied. In subsequent studies, ethacrynic acid at 1 µM was toxic to only 2 of 54 (4%) tumor specimens. Significant enhancement for doxorubicin or nitrogen mustard was confined to lymphatic malignancies and to normal peripheral blood lymphocytes. Interspecimen variability was observed, with no enhancement in most individual specimens, 2-fold enhancement in some specimens, and 4-fold enhancement in occasional specimens. Clinical trials will be required to determine whether the observed in vitro activity for ethacrynic acid is associated with clinical benefit in unselected or assay-selected patients.

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Authors and Affiliations

  1. Oncotech Inc., 1791 Kaiser Avenue, 92714, Irvine, CA

    Robert A. Nagourney, John C. Messenger, David H. Kern & Larry M. Weisenthal

  2. The Memorial Cancer Institute, 92714, Long Beach, CA

    Robert A. Nagourney & John C. Messenger

  3. Division of Hematology/Oncology, Department of Medicine, The University of California, 92714, Irvine, CA, USA

    Robert A. Nagourney

Authors
  1. Robert A. Nagourney
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  2. John C. Messenger
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  3. David H. Kern
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  4. Larry M. Weisenthal
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This work was supported in part by a grant from the Memorial Foundation of Long Beach

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Nagourney, R.A., Messenger, J.C., Kern, D.H. et al. Enhancement of anthracycline and alkylator cytotoxicity by ethacrynic acid in primary cultures of human tissues. Cancer Chemother Pharmacol 26, 318–322 (1990). https://doi.org/10.1007/BF02897285

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  • DOI: https://doi.org/10.1007/BF02897285

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