Arsenic trioxide as a treatment for myelodysplastic syndrome

Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Current Hematologic Malignancy Reports (Impact Factor: 2.2). 03/2006; 1(1):34-8. DOI: 10.1007/s11899-006-0015-6
Source: PubMed


Myelodysplastic syndrome (MDS) is a heterogeneous bone marrow disorder primarily affecting older adults, for whom the only curative therapy, bone marrow transplantation, is rarely an option. New therapies, or novel applications of historical therapies, are desperately needed. Arsenic trioxide (ATO), which acts through proapoptotic, antiproliferative, and antiangiogenesis mechanisms, has been used successfully to treat a variety of hematologic malignancies, including MDS. As monotherapy or in combination with other agents, it can effect hematologic improvement in 22% to 26% of patients, with tolerable side effects. MDS patients whose cells express the EVI1 mutation in particular may derive benefit from this therapy.

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    • "The arsenic-induced apoptosis occurs through direct effects on mitochondria, causing the release of apoptotic proteins into the cytosol and the activation of caspases. Preliminary in vitro studies have also extended the potential anticancer effect (Li et al., 2007; Sekeres, 2006) of arsenic to non-APL leukemias, lymphoid malignancies, and other cancers. In vitro and in vivo studies have consistently demonstrated that arsenic can exert a broad spectrum of anticancer effects by induction of apoptosis, inhibition of cell proliferation, antiangiogenesis, and possible immunomodulation. "
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    • "Lenalidomide , an immunomodulatory drug derived from thalidomide , has been recently approved by the Food and Drug Administration ( FDA ) and is indicated for the treatment of MDS in patients with chromosome 5q deletion . Other agents such as imatinib and tipifarnib are currently being evaluated in clinical trials ( Cortes et al 2003 ; Feldman 2005 ; Sekeres 2005 ; Jabbour and Giles 2005 ) . Some of the therapies farthest along in development are the hypomethylating agents decitabine and azacitidine , both of which have been recently approved by the FDA for the treatment of MDS . "
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    ABSTRACT: Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and a propensity to transform into acute myeloid leukemia. There are few treatment options available for patients with MDS. Studies into the molecular biology of MDS have demonstrated abnormal patterns of DNA methylation that lead to silencing of tumor-suppressor genes. Hypomethylating agents are compounds that have the potential to reverse the aberrant DNA methylation and increase the expression of silenced genes, leading to cellular differentiation and/or apoptosis. Decitabine is a cytidine analogue that has activity as a hypomethylating agent and has been evaluated in the therapy of patients with high-risk MDS. Several studies have confirmed the clinical activity of low-dose decitabine in patients with high-risk MDS, leading to responses in approximately 50% of patients, with low treatment-related mortality. Responses have even been seen in patients with high-risk cytogenetic abnormalities, and some studies have demonstrated increased re-expression of genes that were previously silenced by hypermethylation, such as CDKN2B/p15INK4B. There are still some issues concerning the ideal dose and schedule of decitabine for treating patients with MDS. This article focuses on the most recent clinical studies of decitabine for therapy of MDS.
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