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Approach to New Therapeutics: Investigation by the Use of MDS-derived Cell Lines.
MedLine Citation:
PMID:  22571700     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Myelodysplastic syndromes (MDS) are a group of aquired hematopoietic disorders characterized by ineffective hematopoiesis, and increased risk of progression of acute myeloid leukemia. For a long period of time, the standard therapy for MDS was hematopoietic stem cell transplantation, however DNA methyltransferase inhibitors (DNMT inhibitors) including decitabine (DAC) and azacitidine (AZA), and lenalidomide, a derivative of thalidomide have been highlighted as new chemotherapeutic agents for MDS. However, the underlying mechanisms of action of these drugs have not been fully defined yet. Therefore, we investigated the in vitro effects of DNMT inhibitors and lenalidomide on an MDS-derived cell line, MDS92 and its blastic subline MDS-L, both of which carry del(5q). MDS-L cells were found to be quite sensitive to DAC, which induced to cell death through DNA damage-mediated G2 arrest via p53-independent pathways. Gene expression profiling suggested that DAC affects biogroups representing hematological systems, cellular development, cell death and apoptosis. Next, we examined the effects of lenalidomide on MDS-L. Cell growth was inhibited and multinucleated cells were frequently formed prior to cell death by lenalidomide treatment. Time-lapse microscopic observation and DNA ploidy analysis revealed that lenalidomide does not affect DNA synthesis itself but inhibits cytokinesis of MDS-L cells. The gene expression profiling showed decreased expression of M phase-related genes. These data contribute to the understanding of action mechanisms of lenalidomide on MDS with del(5q).
Authors:
Takayuki Tsujioka; Akihito Matsuoka; Yumi Tohyama; Kaoru Tohyama
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-7
Journal Detail:
Title:  Current pharmaceutical design     Volume:  -     ISSN:  1873-4286     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9602487     Medline TA:  Curr Pharm Des     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Laboratory Medicine, Kawasaki Medical School, Okayama 701-0192, Japan. ktohyama@med.kawasaki-m.ac.jp.
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