Cargando…
Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity
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 effi...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534156/ https://www.ncbi.nlm.nih.gov/pubmed/23154431 http://dx.doi.org/10.1038/cgt.2012.83 |
_version_ | 1782475283841941504 |
---|---|
author | Yuan, Z Syrkin, G Adem, A Geha, R Pastoriza, J Vrikshajanani, C Smith, T Quinn, T J Alemu, G Cho, H Barrett, C J Arap, W Pasqualini, R Libutti, S K |
author_facet | Yuan, Z Syrkin, G Adem, A Geha, R Pastoriza, J Vrikshajanani, C Smith, T Quinn, T J Alemu, G Cho, H Barrett, C J Arap, W Pasqualini, R Libutti, S K |
author_sort | Yuan, Z |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3534156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-35341562013-01-02 Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity Yuan, Z Syrkin, G Adem, A Geha, R Pastoriza, J Vrikshajanani, C Smith, T Quinn, T J Alemu, G Cho, H Barrett, C J Arap, W Pasqualini, R Libutti, S K Cancer Gene Ther Original Article 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. Nature Publishing Group 2013-01 2012-11-16 /pmc/articles/PMC3534156/ /pubmed/23154431 http://dx.doi.org/10.1038/cgt.2012.83 Text en Copyright © 2013 Nature America, Inc. http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Original Article Yuan, Z Syrkin, G Adem, A Geha, R Pastoriza, J Vrikshajanani, C Smith, T Quinn, T J Alemu, G Cho, H Barrett, C J Arap, W Pasqualini, R Libutti, S K Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
title | Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
title_full | Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
title_fullStr | Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
title_full_unstemmed | Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
title_short | Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
title_sort | blockade of inhibitors of apoptosis (iaps) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534156/ https://www.ncbi.nlm.nih.gov/pubmed/23154431 http://dx.doi.org/10.1038/cgt.2012.83 |
work_keys_str_mv | AT yuanz blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT syrking blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT adema blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT gehar blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT pastorizaj blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT vrikshajananic blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT smitht blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT quinntj blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT alemug blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT choh blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT barrettcj blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT arapw blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT pasqualinir blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity AT libuttisk blockadeofinhibitorsofapoptosisiapsincombinationwithtumortargeteddeliveryoftumornecrosisfactoraleadstosynergisticantitumoractivity |