| Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines. | |
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MedLine Citation:
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PMID: 22821746 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Abid R Mattoo; David J FitzGerald |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2012-08-16 |
Journal Detail:
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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:
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Created Date: 2012-12-20 Completed Date: 2013-02-20 Revised Date: 2013-05-24 |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 978-87 Citation Subset: IM |
Copyright Information:
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Published 2012 UICC. |
Affiliation:
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Biotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, HHS, Bethesda, MD 20819, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aniline Compounds
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pharmacology,
therapeutic use* Animals Biphenyl Compounds / pharmacology* Caspase 3 / metabolism Caspase 7 / metabolism Cell Line, Tumor Drug Resistance, Neoplasm / drug effects Drug Synergism Humans Immunotoxins / pharmacology, therapeutic use* Mice Mice, Inbred BALB C Mice, Nude 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* |
| Chemical | |
Reg. No./Substance:
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0/ABT-737; 0/Aniline Compounds; 0/Biphenyl Compounds; 0/Immunotoxins; 0/Nitrophenols; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Transferrin; 0/Sulfonamides; 0/myeloid cell leukemia sequence 1 protein; 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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