Document Detail


Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity.
MedLine Citation:
PMID:  23154431     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the current study, we examined whether the combination of tumor vasculature-targeted gene therapy with adeno-associated virus bacteriophage-tumor necrosis factor-α (AAVP-TNF-α) and/or the orally administered LCL161, an antagonist of inhibitors of apoptosis proteins (IAPs), enhanced antitumor efficacy without systemic toxicity. M21 human melanoma xenografts were grown subcutaneously in nude mice. Mice were treated according to one of four treatment regimens: AAVP-TNF-α alone (AAVP-TNF-α plus sodium acetate-acetic acid (NaAc) buffer) via tail vein injection; LCL161 alone (phosphate-buffered saline (PBS) plus LCL161) via oral gavage; AAVP-TNF-α plus LCL161; and PBS plus NaAc Buffer as a control group. Tumor volume, survival and toxicity were analyzed. AAVP trafficking and TNF-α production in vivo were detected on days 7 and 21 by real-time PCR, enzyme-linked immunosorbent assay and immunofluorescence. The levels of apoptosis and activation of caspases were assessed on days 7 and 21 by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) and immunofluorescence assays. Our results showed that the combination of AAVP-TNF-α and LCL161 significantly inhibited tumor growth and prolonged survival in mice with melanoma xenografts. The combination of AAVP-TNF-α and LCL161 was also significantly more effective than either agent alone, showing a synergistic effect without systemic toxicity.
Authors:
Z Yuan; G Syrkin; A Adem; R Geha; J Pastoriza; C Vrikshajanani; T Smith; T J Quinn; G Alemu; H Cho; C J Barrett; W Arap; R Pasqualini; S K Libutti
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-16
Journal Detail:
Title:  Cancer gene therapy     Volume:  20     ISSN:  1476-5500     ISO Abbreviation:  Cancer Gene Ther.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-28     Completed Date:  2013-05-27     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  9432230     Medline TA:  Cancer Gene Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  46-56     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Antineoplastic Agents / administration & dosage*,  pharmacology
Apoptosis
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation
Combined Modality Therapy
Dependovirus / genetics
Drug Resistance, Neoplasm
Female
Genetic Therapy
Humans
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*,  genetics,  metabolism
Melanoma / blood supply,  pathology,  therapy*
Mice
Mice, Nude
Organ Specificity
Proteolysis
Thiazoles / administration & dosage*,  pharmacology
Transduction, Genetic
Tumor Burden
Tumor Necrosis Factor-alpha / biosynthesis,  genetics*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
P30 CA013330/CA/NCI NIH HHS; R01 CA088106/CA/NCI NIH HHS; R01 CA103830/CA/NCI NIH HHS; U54 CA151668/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Inhibitor of Apoptosis Proteins; 0/LCL161; 0/Thiazoles; 0/Tumor Necrosis Factor-alpha; EC 3.4.22.-/Caspases
Comments/Corrections

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