In vitro activity of dimethylarsinic acid against human leukemia and multiple myeloma cell lines.
OBJECTIVE
Arsenic trioxide (As(2)O(3)), an inorganic arsenic compound, has recently been approved for the treatment of relapsed or refractory acute promyelocytic leukemia. However, systemic toxicity associated with As(2)O(3) treatment remains a problem. Inorganic arsenic is detoxified in vivo by methylation reactions into organic arsenic compounds that are less toxic.


RESULTS
We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As(2)O(3), against a panel of eight leukemia and multiple myeloma cell lines. As(2)O(3) was tested in comparison. In clonogenic assay, the average concentration of DMAA that suppressed cell colony growth by 50% was 0.5-1 m M, while for As(2)O(3) it was on average 1-2 microM. At those concentrations DMAA and As(2)O(3) had significantly less effect on colony growth of normal progenitor cells. Cytotoxic doses of DMAA and As(2)O(3) 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 As(2)O(3), but significantly less effect on normal progenitor cells. DMAA, unlike As(2)O(3), 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 As(2)O(3). Evaluation of novel organic arsenic that would combine the high efficacy of As(2)O(3) and the low toxicity of DMAA is warranted.
Duzkale
Hatice
H
Department of Special Medical Education Programs, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Jilani
Iman
I
Orsolic
Nada
N
Zingaro
Ralph A
RA
Golemovic
Mirna
M
Giles
Francis J
FJ
Kantarjian
Hagop
H
Albitar
Maher
M
Freireich
Emil J
EJ
Verstovsek
Srdan
S
D002101:Cacodylic Acid / Q000494:pharmacology*; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006540:Herbicides / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D009101:Multiple Myeloma / Q000473:pathology*; D014407:Tumor Cells, Cultured
D006540:Herbicides; D002101:Cacodylic Acid