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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2009

01-05-2009 | Original Article

Lack of toxicity of a STAT3 decoy oligonucleotide

Authors: Malabika Sen, Patricia J. Tosca, Christa Zwayer, Michael J. Ryan, Jerry D. Johnson, Katherine A. B. Knostman, Patricia C. Giclas, James O. Peggins, Joseph E. Tomaszewski, Timothy P. McMurray, Changyou Li, Michael S. Leibowitz, Robert L. Ferris, William E. Gooding, Sufi M. Thomas, Daniel E. Johnson, Jennifer R. Grandis

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2009

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Abstract

Background

STAT3 overexpression has been detected in several cancers including head and neck squamous cell carcinoma (HNSCC). Previous studies using intratumoral administration of a STAT3 decoy oligonucleotide that abrogates STAT3-mediated gene transcription in preclinical cancer models have demonstrated antitumor efficacy. This study was conducted to observe the toxicity and biologic effects of the STAT3 decoy in a non-human primate model, in anticipation of initiating a clinical trial in HNSCC patients.

Methods

Three study groups (two monkeys/sex/group) were administered a single intramuscular injection of low dose of STAT3 decoy (0.8 mg total dose/monkey), high dose of STAT3 decoy (3.2 mg total dose/monkey) or vehicle control (PBS alone) on day 1 and necropsies were performed on days 2 and 15 (one monkey/sex/group/day). Low and high doses of the decoy were administered in the muscle in a volume of 0.9 ml. Tissue and blood were harvested for toxicology and biologic analyses.

Results

Upon observation, the STAT3 decoy-treated animals exhibited behavior that was similar to the vehicle control group. Individual animal body weights remained within 1% of pretreatment weights throughout the study. Hematological parameters were not significantly different between the control and the treatment groups. Clinical chemistry fluctuations were considered within normal limits and were not attributed to the STAT3 decoy. Assessment of complement activation breakdown product (Bb) levels demonstrated no activation of the alternative pathway of complement in any animal at any dose level. At necropsy, there were no gross or microscopic findings attributed to STAT3 decoy in any organ examined. STAT3 target gene expression at the injection site revealed decreased Bcl-XL and cyclin D1 expression levels in the animals treated with high dose of STAT3 decoy compared to the animals injected with low dose of STAT3 decoy or the vehicle as control.

Conclusion

Based on these findings, the no-observable-adverse-effect-level (NOAEL) was greater than 3.2 mg/kg when administered as a single dose to male and female Cynomolgus monkeys. Plans are underway to test the safety and biologic effects of intratumoral administration of the STAT3 decoy in HNSCC patients.
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Metadata
Title
Lack of toxicity of a STAT3 decoy oligonucleotide
Authors
Malabika Sen
Patricia J. Tosca
Christa Zwayer
Michael J. Ryan
Jerry D. Johnson
Katherine A. B. Knostman
Patricia C. Giclas
James O. Peggins
Joseph E. Tomaszewski
Timothy P. McMurray
Changyou Li
Michael S. Leibowitz
Robert L. Ferris
William E. Gooding
Sufi M. Thomas
Daniel E. Johnson
Jennifer R. Grandis
Publication date
01-05-2009
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0823-6

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