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Abstract

Abstract

Imatinib is currently the standard drug used in the treatment of CML patients. However, imatinib is not curative since most patients who discontinue therapy will relapse. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, prior exposure to IFN allowed Imatinib discontinuation in some CML patients. Arsenic trioxide inhibits the proliferation of BCR-ABL-expressing cells.

We have investigated the effects of the combination arsenic/IFN on the proliferation of CML cell lines. We found that IFN alone had minimal effect. Arsenic alone significantly decreased their proliferation in a time and dose-dependent manner. Interestingly, the addition of IFN to arsenic was synergistic in AR230 and additive in K562. This synergistic effect between IFN and arsenic was accompanied by dose-dependent apoptosis as evidenced by annexin V staining, TUNEL positivity and caspase activation. Colony-forming assay was performed on bone marrow and CD34+ cells collected from CML patients. Interestingly, arsenic and IFN produced a synergistic decrease in myeloid colony formation, especially when compared to Imatinib.

Preliminary results of an in vivo study using the retroviral transduction CML mouse model showed prolonged survival of secondary recipients that received cells from primary leukemic mice treated with arsenic/IFN, as compared to those that received cells from untreated controls. These results suggest that arsenic and IFN synergize to inhibit proliferation, induce apoptosis and target dormant CML stem cells that are spared by Imatinib.

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/content/papers/10.5339/qfarf.2011.BMO2
2011-11-20
2020-09-22
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