Document Detail


Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.
MedLine Citation:
PMID:  23321252     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048.
Authors:
Jing Chen; Cynthia A Pise-Masison; Joanna H Shih; John C Morris; John E Janik; Kevin C Conlon; Anne Keating; Thomas A Waldmann
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2013-01-15
Journal Detail:
Title:  Blood     Volume:  121     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-13     Revised Date:  2014-03-17    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2029-37     Citation Subset:  AIM; IM    
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00061048
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MeSH Terms
Descriptor/Qualifier:
Adult
Animals
Antibodies, Monoclonal, Humanized / administration & dosage*,  pharmacology
Antineoplastic Combined Chemotherapy Protocols / pharmacology,  therapeutic use*
Cells, Cultured
Drug Synergism
Humans
Imidazoles / administration & dosage*,  pharmacology
Inhibitor of Apoptosis Proteins / antagonists & inhibitors,  genetics
Leukemia-Lymphoma, Adult T-Cell / drug therapy*,  genetics,  pathology
Mice
Mice, Inbred NOD
Mice, SCID
Naphthoquinones / administration & dosage*,  pharmacology
Substrate Specificity
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal, Humanized; 0/BIRC5 protein, human; 0/Imidazoles; 0/Inhibitor of Apoptosis Proteins; 0/Naphthoquinones; 0/YM 155; 3A189DH42V/alemtuzumab
Comments/Corrections

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