Document Detail


Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia.
MedLine Citation:
PMID:  23393050     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Survival in infants younger than 1 year who have acute lymphoblastic leukemia (ALL) is inferior whether MLL is rearranged (R) or germline (G). MLL translocations confer chemotherapy resistance, and infants experience excess complications. We characterized in vitro sensitivity to the pan-antiapoptotic BCL-2 family inhibitor obatoclax mesylate in diagnostic leukemia cells from 54 infants with ALL/bilineal acute leukemia because of the role of prosurvival BCL-2 proteins in resistance, their imbalanced expression in infant ALL, and evidence of obatoclax activity with a favorable toxicity profile in early adult leukemia trials. Overall, half maximal effective concentrations (EC50s) were lower than 176 nM (the maximal plasma concentration [Cmax] with recommended adult dose) in 76% of samples, whether in MLL-AF4, MLL-ENL, or other MLL-R or MLL-G subsets, and regardless of patients' poor prognostic features. However, MLL status and partner genes correlated with EC50. Combined approaches including flow cytometry, Western blot, obatoclax treatment with death pathway inhibition, microarray analyses, and/or electron microscopy indicated a unique killing mechanism involving apoptosis, necroptosis, and autophagy in MLL-AF4 ALL cell lines and primary MLL-R and MLL-G infant ALL cells. This in vitro obatoclax activity and its multiple killing mechanisms across molecular cytogenetic subsets provide a rationale to incorporate a similarly acting compound into combination strategies to combat infant ALL.
Authors:
Karen A Urtishak; Alena Y Z Edwards; Li-San Wang; Amanda Hudome; Blaine W Robinson; Jeffrey S Barrett; Kajia Cao; Lori Cory; Jonni S Moore; Andrew D Bantly; Qian-Chun Yu; I-Ming L Chen; Susan R Atlas; Cheryl L Willman; Mondira Kundu; Andrew J Carroll; Nyla A Heerema; Meenakshi Devidas; Joanne M Hilden; ZoAnn E Dreyer; Stephen P Hunger; Gregory H Reaman; Carolyn A Felix
Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-07
Journal Detail:
Title:  Blood     Volume:  121     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-05     Completed Date:  2013-05-28     Revised Date:  2014-04-10    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2689-703     Citation Subset:  AIM; IM    
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00933985
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects*
Autophagy / drug effects*
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Leukemic / drug effects
Humans
Infant
Infant, Newborn
Myeloid-Lymphoid Leukemia Protein / genetics
Necrosis / drug therapy
Oncogene Proteins, Fusion / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*,  genetics,  pathology*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Pyrroles / therapeutic use*
Grant Support
ID/Acronym/Agency:
CA98543/CA/NCI NIH HHS; K08HL084199/HL/NHLBI NIH HHS; R25CA101871/CA/NCI NIH HHS; U10 CA98413/CA/NCI NIH HHS; U24 CA114766/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/MLL protein, human; 0/MLL-AF4 fusion protein, human; 0/MLL-ENL oncoprotein, human; 0/Oncogene Proteins, Fusion; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrroles; 0/obatoclax; 149025-06-9/Myeloid-Lymphoid Leukemia Protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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