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

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.