CoChat
Sign Up
Cited by 53Cytokine Signaling Pathways and InteractionsRNA Interference and Gene DeliveryHead and Neck Cancer Studies

Lack of toxicity of a STAT3 decoy oligonucleotide

Open access
Sen, Malabika, Tosca, Patricia J., Zwayer, Christa, Ryan, Michael J., Johnson, Jerry D., Knostman, Katherine A. B., Giclas, Patricia C., Peggins, James O. +9 more·2009·Cancer Chemotherapy and Pharmacology
DOI 10.1007/s00280-008-0823-6PMC PMC3422883
Open this paper in CoChat — free account

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-X(L) 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s00280-008-0823-6

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Toxicology studies in nonhuman primates demonstrate a lack of toxicity of a STAT3 decoy oligonucleotide.

    “Indeed, toxicology studies in nonhuman primates demonstrate a lack of toxicity of a STAT3 decoy oligonucleotide.107”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [107]

    The Discussion reports no evidence of systemic or organ-specific toxicity after a single intramuscular injection in cynomolgus monkeys. But the Statistical analysis section says the small, observational study cannot establish that the decoy is safe; the unqualified claim of a lack of toxicity overstates what this study demonstrated. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 29

  1. [1]Barton BE Karras JG Murphy TF Barton A Huang HF Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines Mol Cancer Ther 2004 3 11 20 14749471
  2. [2]Bhasin D Cisek K Pandharkar T Regan N Li C Pandit B Lin J Li PK Design, synthesis, and studies of small molecule STAT3 inhibitors Bioorg Med Chem Lett 2008 18 391 395 18006313
  3. [3]Bromberg JF Wrzeszczynska MH Devgan G Zhao Y Pestell RG Albanese C Darnell JE Jr Stat3 as an oncogene Cell 1999 98 295 303 10458605
  4. [4]Chan KS Sano S Kiguchi K Anders J Komazawa N Takeda J DiGiovanni J Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis J Clin Invest 2004 114 720 728 15343391 PMC514583
  5. [5]Crooke RM Graham MJ Martin MJ Lemonidis KM Wyrzykiewiecz T Cummins LL Metabolism of antisense oligonucleotides in rat liver homogenates J Pharmacol Exp Ther 2000 292 140 149 10604941
  6. [7]Dean NM Bennett CF Antisense oligonucleotide-based therapeutics for cancer Oncogene 2003 22 9087 9096 14663487
  7. [8]Dudoit S van der Laan MJ Multiple testing procedures with applications to genomics 2008 New York Springer Science + Business Media New York
  8. [9]Galbraith WM Hobson WC Giclas PC Schechter PJ Agrawal S Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey Antisense Res Dev 1994 4 201 206 7849490
  9. [10]Gao LF Xu DQ Wen LJ Zhang XY Shao YT Zhao XJ Inhibition of STAT3 expression by siRNA suppresses growth and induces apoptosis in laryngeal cancer cells Acta Pharmacol Sin 2005 26 377 383 15715937
  10. [11]Grandis JR Drenning SD Zeng Q Watkins SC Melhem MF Endo S Johnson DE Huang L He Y Kim JD Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo Proc Natl Acad Sci USA 2000 97 4227 4232 10760290 PMC18206
  11. [12]Haura EB Zheng Z Song L Cantor A Bepler G Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer Clin Cancer Res 2005 11 8288 8294 16322287
  12. [13]Henry SP Monteith D Bennett F Levin AA Toxicological and pharmacokinetic properties of chemically modified antisense oligonucleotide inhibitors of PKC-alpha and C-raf kinase Anticancer Drug Des 1997 12 409 420 9236856
  13. [14]Hoel AW Conte MS Edifoligide: a transcription factor decoy to modulate smooth muscle cell proliferation in vein bypass Cardiovasc Drug Rev 2007 25 221 234 17919257
  14. [15]Hottiger MO Felzien LK Nabel GJ Modulation of cytokine- induced HIV gene expression by competitive binding of transcription factors to the coactivator p300 EMBO J 1998 17 3124 3134 9606194 PMC1170651
  15. [16]Jing N Sha W Li Y Xiong W Tweardy DJ Rational drug design of G-quartet DNA as anti-cancer agents Curr Pharm Des 2005 11 2841 2854 16101441
  16. [17]Jing N Tweardy DJ Targeting Stat3 in cancer therapy Anticancer Drugs 2005 16 601 607 15930886
  17. [18]Lai SY Childs EE Xi S Coppelli FM Gooding WE Wells A Ferris RL Grandis JR Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma Oncogene 2005 24 4442 4449 15856028
  18. [19]Leeman RJ Lui VW Grandis JR STAT3 as a therapeutic target in head and neck cancer Expert Opin Biol Ther 2006 6 231 241 16503733
  19. [21]Lui VW Boehm AL Koppikar P Leeman RJ Johnson D Ogagan M Childs E Freilino M Grandis JR Antiproliferative mechanisms of a transcription factor decoy targeting signal transducer and activator of transcription (STAT) 3: the role of STAT1 Mol Pharmacol 2007 71 1435 1443 17325127
  20. [22]Mayr S Welte T Windegger M Lechner J May P Heinrich PC Horn F Doppler W Selective coupling of STAT factors to the mouse prolactin receptor Eur J Biochem 1998 258 784 793 9874248
  21. [23]Mora LB Buettner R Seigne J Diaz J Ahmad N Garcia R Bowman T Falcone R Fairclough R Cantor A Muro-Cacho C Livingston S Karras J Pow-Sang J Jove R Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells Cancer Res 2002 62 6659 6666 12438264
  22. [24]Novak EM Metzger M Chammas R da Costa M Dantas K Manabe C Pires J de Oliveira AC Bydlowski SP Downregulation of TNF-alpha and VEGF expression by Sp1 decoy oligodeoxynucleotides in mouse melanoma tumor Gene Ther 2003 10 1992 1997 14528323
  23. [25]Rubin Grandis J Zeng Q Drenning SD Epidermal growth factor receptor-mediated stat3 signaling blocks apoptosis in head and neck cancer Laryngoscope 2000 110 868 874 10807365
  24. [26]Sun Z Yao Z Liu S Tang H Yan X An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer Immunobiology 2006 211 199 209 16530087
  25. [27]Takeda K Noguchi K Shi W Tanaka T Matsumoto M Yoshida N Kishimoto T Akira S Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality Proc Natl Acad Sci USA 1997 94 3801 3804 9108058 PMC20521
  26. [28]Tan M Lan KH Yao J Lu CH Sun M Neal CL Lu J Yu D Selective inhibition of ErbB2-overexpressing breast cancer in vivo by a novel TAT-based ErbB2-targeting signal transducers and activators of transcription 3-blocking peptide Cancer Res 2006 66 3764 3772 16585203
  27. [29]Tomita N Morishita R Lan HY Yamamoto K Hashizume M Notake M Toyosawa K Fujitani B Mu W Nikolic-Paterson DJ Atkins RC Kaneda Y Higaki J Ogihara T In vivo administration of a nuclear transcription factor-kappaB decoy suppresses experimental crescentic glomerulonephritis J Am Soc Nephrol 2000 11 1244 1252 10864580
  28. [30]Xi S Gooding WE Grandis JR In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy Oncogene 2005 24 970 979 15592503
  29. [31]Zhang X Zhang J Wang L Wei H Tian Z Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice BMC Cancer 2007 7 149 17683579 PMC1988829

Cited by

Sorted by citations

Authors
Sen, M., Tosca, P. J., Zwayer, C., Ryan, M. J., Johnson, J. D., Knostman, K. A. B., Giclas, P. C., Peggins, J. O., Tomaszewski, J. E., McMurray, T. P., Li, C., Leibowitz, M. S., Ferris, R. L., Gooding, W. E., Thomas, S. M., Johnson, D. E., & Grandis, J. R.
Affiliations
  • University of Pittsburgh (US)
  • Battelle (US)
  • National Jewish Health (US)
  • UPMC Hillman Cancer Center (US)
Corresponding author
Grandis, Jennifer R.
ORCID
Venue
Cancer Chemotherapy and Pharmacology
Publisher
Springer Science and Business Media LLC
Published
2008-09-03
Volume
63
Issue
6
Pages
983-995
ISSN
  • 0344-5704 (ISSN-L)
  • 1432-0843
DOI
10.1007/s00280-008-0823-6
PMC
PMC3422883
OpenAlex
W2088229999
Cited by
53
References
2
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 3 · 2019: 2 · 2018: 3 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 8 · 2012: 6
FWCI
1.94
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cancer Chemotherapy and Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA101840, P50CA097190)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
Keywords
STAT3, head and neck squamous cell carcinoma, toxicity, non-human primate safety, Macaca fascicularis, no-observed-adverse-effect level, intramuscular injection, complement activation, Bcl-xL, cyclin D1, cancer gene therapy
MeSH terms
Animals, Female, Injections, Intramuscular, Macaca fascicularis, Male, Oligonucleotides, Tubulin, Gene Expression, Toxicity Tests, No-Observed-Adverse-Effect Level, Cyclin D1, STAT3 Transcription Factor, bcl-X Protein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review