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In vitro activity of dimethylarsinic acid against human leukemia and multiple myeloma cell lines

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Abstract

Purpose

Arsenic trioxide (As2O3), an inorganic arsenic compound, has recently been approved for the treatment of relapsed or refractory acute promyelocytic leukemia. However, systemic toxicity associated with As2O3 treatment remains a problem. Inorganic arsenic is detoxified in vivo by methylation reactions into organic arsenic compounds that are less toxic.

Methods and results

We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As2O3, against a panel of eight leukemia and multiple myeloma cell lines. As2O3 was tested in comparison. In clonogenic assay, the average concentration of DMAA that suppressed cell colony growth by 50% was 0.5–1 mM, while for As2O3 it was on average 1–2 μM. At those concentrations DMAA and As2O3 had significantly less effect on colony growth of normal progenitor cells. Cytotoxic doses of DMAA and As2O3 in 3-day trypan blue dye exclusion assay experiments were similar to doses effective in clonogenic assay. Assessment of apoptosis by annexin V assay revealed a high rate of apoptosis in all cell lines treated with DMAA and As2O3, but significantly less effect on normal progenitor cells. DMAA, unlike As2O3, had no effect on the maturation of leukemic cells.

Conclusions

DMAA exerts differential antiproliferative and cytotoxic activity against leukemia and multiple myeloma cells, with no significant effect on normal progenitor cells. However, concentrations of DMAA needed to achieve such efficacy are up to 1000 times those of As2O3. Evaluation of novel organic arsenic that would combine the high efficacy of As2O3 and the low toxicity of DMAA is warranted.

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Authors and Affiliations

  1. Department of Special Medical Education Programs, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Hatice Duzkale & Emil J. Freireich

  2. Department of Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Iman Jilani & Maher Albitar

  3. Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    Nada Orsolic, Mirna Golemovic, Francis J. Giles, Hagop Kantarjian & Srdan Verstovsek

  4. Department of Chemistry, Texas A&M University, College Station, Texas, USA

    Ralph A. Zingaro

Authors
  1. Hatice Duzkale
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  2. Iman Jilani
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  3. Nada Orsolic
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  4. Ralph A. Zingaro
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  5. Mirna Golemovic
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  6. Francis J. Giles
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  7. Hagop Kantarjian
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  8. Maher Albitar
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  9. Emil J. Freireich
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  10. Srdan Verstovsek
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Corresponding author

Correspondence to Srdan Verstovsek.

Additional information

This work was supported in part by The Robert A. Welch Foundation.

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Duzkale, H., Jilani, I., Orsolic, N. et al. In vitro activity of dimethylarsinic acid against human leukemia and multiple myeloma cell lines. Cancer Chemother Pharmacol 51, 427–432 (2003). https://doi.org/10.1007/s00280-003-0588-x

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  • DOI: https://doi.org/10.1007/s00280-003-0588-x

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