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

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.

• 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
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 20 Issue 1 Pg. 46-56 (Jan 2013) ISSN: 1476-5500 [Electronic] England
• PMID: 23154431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Inhibitor of Apoptosis Proteins
• LCL161
• Thiazoles
• Tumor Necrosis Factor-alpha
• Caspases

Topics

• 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