Document Detail

Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines.
MedLine Citation:
PMID:  22821746     Owner:  NLM     Status:  MEDLINE    
Synergistic killing was achieved when Small Cell Lung Cancer (SCLC) cell lines were incubated with ABT-263 and an immunotoxin directed to the transferrin receptor. SCLC lines are variably sensitive to the BH-3 only peptide mimetic, ABT-263. To determine their sensitivity to toxin-based reagents, we incubated four representative SCLC lines with a model Pseudomonas exotoxin-based immunotoxin directed to the transferrin receptor. Remarkably in 4-of-4 lines, there was little evidence of immunotoxin-mediated cytotoxicity despite near complete inhibition of protein synthesis. However, when combinations of ABT-263 and immunotoxin were added to the ABT-263-resistant cell lines (H196 and H69AR), there was synergistic killing as evidenced by increased activation of caspase 3/7, annexin V staining, and loss of cell integrity. Synergistic killing was evident at 6 hr and correlated with loss of Mcl-1. This synergy was also noted when the closely related compound ABT-737 was combined with the same immunotoxin. To establish that the synergy seen in tissue culture could be achieved in vivo, H69AR cells were grown as tumors in nude mice and shown to be susceptible to the killing action of an immunotoxin-ABT-737 combination but not to either agent alone. When immunotoxin-ABT combinations were added to ABT-263-sensitive lines (H146 and H1417), killing was additive. Our data support combination approaches for treating ABT-263-resistant SCLC with ABT-263 and a second agent that provides synergistic killing action.
Abid R Mattoo; David J FitzGerald
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-08-16
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  132     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2012-12-20     Completed Date:  2013-02-20     Revised Date:  2014-02-18    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  978-87     Citation Subset:  IM    
Copyright Information:
Published 2012 UICC.
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MeSH Terms
Aniline Compounds / pharmacology,  therapeutic use*
Biphenyl Compounds / pharmacology*
Caspase 3 / metabolism
Caspase 7 / metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Synergism
Immunotoxins / pharmacology,  therapeutic use*
Mice, Inbred BALB C
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein
Nitrophenols / pharmacology*
Piperazines / pharmacology
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors,  biosynthesis
Receptors, Transferrin / immunology
Small Cell Lung Carcinoma / drug therapy*
Sulfonamides / pharmacology*,  therapeutic use*
Grant Support
Z01 BC008757-21/BC/NCI NIH HHS
Reg. No./Substance:
0/ABT-737; 0/Aniline Compounds; 0/Biphenyl Compounds; 0/Immunotoxins; 0/Mcl1 protein, mouse; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/Nitrophenols; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Transferrin; 0/Sulfonamides; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; XKJ5VVK2WD/navitoclax

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

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