Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity

Z. Yuan, Grigory 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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)46-56
Number of pages11
JournalCancer Gene Therapy
Volume20
Issue number1
DOIs
StatePublished - Jan 2013

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Dependovirus
Bacteriophages
Tumor Necrosis Factor-alpha
Apoptosis
Neoplasms
Heterografts
Fluorescent Antibody Technique
Melanoma
Buffers
Phosphates
Inhibitor of Apoptosis Proteins
Sodium Acetate
Survival
DNA Nucleotidylexotransferase
In Situ Nick-End Labeling
Caspases
Tumor Burden
Nude Mice
Acetic Acid
Genetic Therapy

Keywords

  • Adeno-associated virus bacteriophage-tumor necrosis factor-a (AAVP-TNF-a)
  • Apoptosis
  • Conventional chemotherapy
  • LCL161
  • Targeted gene therapy

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

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, Grigory; 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.

In: Cancer Gene Therapy, Vol. 20, No. 1, 01.2013, p. 46-56.

Research output: Contribution to journalArticle

Yuan, Z, Syrkin, G, Adem, A, Geha, R, Pastoriza, J, Vrikshajanani, C, Smith, T, Quinn, TJ, Alemu, G, Cho, H, Barrett, CJ, Arap, W, Pasqualini, R & Libutti, SK 2013, 'Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity', Cancer Gene Therapy, vol. 20, no. 1, pp. 46-56. https://doi.org/10.1038/cgt.2012.83
Yuan, Z. ; Syrkin, Grigory ; 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. In: Cancer Gene Therapy. 2013 ; Vol. 20, No. 1. pp. 46-56.
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AU - Geha, R.

AU - Pastoriza, J.

AU - Vrikshajanani, C.

AU - Smith, T.

AU - Quinn, T. J.

AU - Alemu, G.

AU - Cho, H.

AU - Barrett, C. J.

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AU - Pasqualini, R.

AU - Libutti, S. K.

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AB - 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.

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