Arsenic agents have been used in ancient Chinese medicine for several diseases. Among these agents. Arsenic trioxide has recently been reported as an effective agent for the therapy of relapse and refractory Acute Promyelocytic Leukemia. Several clinical phase trials to determine its efficacy on other hematological disorders including other types of leukemia, lymphoma,and multiple myeloma are being performed at different centers. Although the results look favorable, toxic side effects of arsenic trioxide is a problem. Unlike inorganic arsenic agents like arsenic trioxide, no deaths or serious cases of toxicity due to organoarsenicals have been reported in the literature. Therefore, we tested the effect of organic arsenic compound Dimethylarsinic Acid (DMAA) on both cancer cells and normal progenitor cells of bone marrow. We used colony formation assay and Flow Cytometry to determine its effect. DMAA inhibited colony formation on all cell lines tested. The leukemia cell lines NB4 (Acute Promyelocytic Leukemia), HL60 (AML3), KBM3 (Acute Myelomonocytic Leukemia; AML-4), AML-3, KBM5 (Chronic Myelocytic Leukemia-Blast Crisis), K562 (Chronic Myelocytic Leukemia-Blast Crisis) were responsive to DMAA as the same as or higher than their response to arsenic trioxide. The dose used for arsenic trioxide in our experiments was 1 -2 uM, the clinically relevant dose of this agent. Effective DMAA dose ranged from 0.5 mM to 2mM depending on cell line tested. Multiple myeloma cell lines RPMI 8226, ARK, CAG were also affected by DMAA much more than the inhibition shown by arsenic trioxide on these cells. Since the LD50 value of DMAA is much higher than arsenic trioxide, we were not concerned about its higher effective dose whether it would not be clinically relevant. DMAA was more effective than arsenic trioxide also in inducing apoptosis which is assessed by annexin V, at all cell lines tested, while it did not have significant killing effect on normal progenitor cells of bone marrow. Further studies are to be done on other types of hématologie malignancies. According to our in vitro results, DMAA has same or higher effect than arsenic trioxide on caricer cells while sparing normal hematopoetic progenitor cells of bone marrow. We conclude that after confirming its specific toxicity by in vivo animal studies. Dimethylarsinic Acid can be tried in clinical phase studies for the treatment of hématologie malignancies.
Dimethylarsinic acid as an effective compound on hematologic malignancies in vitro / H. Duzkale, I. Jilani, F. Onida, R. Zingaro, L. Baoshun, H. Kantarjian, L. Pagliaro, E. Freireich. - In: BLOOD. - ISSN 0006-4971. - 96:11 Supplement 1(2000 Dec), pp. 115A-115A. ((Intervento presentato al 42. convegno Annual Meeting of the American Society of Hematology tenutosi a S. Francisco, California, USA nel 2000.
Dimethylarsinic acid as an effective compound on hematologic malignancies in vitro
F. Onida;
2000
Abstract
Arsenic agents have been used in ancient Chinese medicine for several diseases. Among these agents. Arsenic trioxide has recently been reported as an effective agent for the therapy of relapse and refractory Acute Promyelocytic Leukemia. Several clinical phase trials to determine its efficacy on other hematological disorders including other types of leukemia, lymphoma,and multiple myeloma are being performed at different centers. Although the results look favorable, toxic side effects of arsenic trioxide is a problem. Unlike inorganic arsenic agents like arsenic trioxide, no deaths or serious cases of toxicity due to organoarsenicals have been reported in the literature. Therefore, we tested the effect of organic arsenic compound Dimethylarsinic Acid (DMAA) on both cancer cells and normal progenitor cells of bone marrow. We used colony formation assay and Flow Cytometry to determine its effect. DMAA inhibited colony formation on all cell lines tested. The leukemia cell lines NB4 (Acute Promyelocytic Leukemia), HL60 (AML3), KBM3 (Acute Myelomonocytic Leukemia; AML-4), AML-3, KBM5 (Chronic Myelocytic Leukemia-Blast Crisis), K562 (Chronic Myelocytic Leukemia-Blast Crisis) were responsive to DMAA as the same as or higher than their response to arsenic trioxide. The dose used for arsenic trioxide in our experiments was 1 -2 uM, the clinically relevant dose of this agent. Effective DMAA dose ranged from 0.5 mM to 2mM depending on cell line tested. Multiple myeloma cell lines RPMI 8226, ARK, CAG were also affected by DMAA much more than the inhibition shown by arsenic trioxide on these cells. Since the LD50 value of DMAA is much higher than arsenic trioxide, we were not concerned about its higher effective dose whether it would not be clinically relevant. DMAA was more effective than arsenic trioxide also in inducing apoptosis which is assessed by annexin V, at all cell lines tested, while it did not have significant killing effect on normal progenitor cells of bone marrow. Further studies are to be done on other types of hématologie malignancies. According to our in vitro results, DMAA has same or higher effect than arsenic trioxide on caricer cells while sparing normal hematopoetic progenitor cells of bone marrow. We conclude that after confirming its specific toxicity by in vivo animal studies. Dimethylarsinic Acid can be tried in clinical phase studies for the treatment of hématologie malignancies.
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