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Molecular Medicine

, Volume 20, Issue 1, pp 46–56 | Cite as

Systemic Administration of a Cyclic Signal Transducer and Activator of Transcription 3 (STAT3) Decoy Oligonucleotide Inhibits Tumor Growth without Inducing Toxicological Effects

  • Malabika Sen
  • Kathleen Paul
  • Maria L. Freilino
  • Hua Li
  • Changyou Li
  • Daniel E. Johnson
  • Lin Wang
  • Julie Eiseman
  • Jennifer R. Grandis
Research Article

Abstract

Hyperactivation of signal transducer and activator of transcription 3 (STAT3) has been linked to tumorigenesis in most malignancies, including head and neck squamous cell carcinoma. Intravenous delivery of a chemically modified cyclic STAT3 decoy oligonucleotide with improved serum and thermal stability demonstrated antitumor efficacy in conjunction with downmodulation of STAT3 target gene expression such as cyclin D1 and Bcl-XL in a mouse model of head and neck squamous cell carcinoma. The purpose of the present study was to determine the toxicity and dose-dependent antitumor efficacy of the cyclic STAT3 decoy after multiple intravenous doses in Foxn1 nu mice in anticipation of clinical translation. The two doses (5 and 10 mg/kg) of cyclic STAT3 decoy demonstrated a significant decrease in tumor volume compared with the control groups (mutant cyclic STAT3 decoy or saline) in conjunction with downmodulation of STAT3 target gene expression. There was no dose-dependent effect of cyclic STAT3 decoy on tumor volume or STAT3 target gene expression. There were no significant changes in body weights between the groups during the dosing period, after the dosing interval or on the day of euthanasia. No hematology or clinical chemistry parameters suggested toxicity of the cyclic STAT3 decoy compared with saline control. No gross or histological pathological abnormalities were noted at necropsy in any of the animals. These findings suggest a lack of toxicity of intravenous administration of a cyclic STAT3 decoy oligonucleotide. In addition, comparable antitumor effects indicate a lack of dose response at the two dose levels investigated.

Notes

Acknowledgments

This work was supported by National Institutes of Health Grants P50CA097190 and R01CA77308 and the American Cancer Society. Research support was provided by Johnson & Johnson and the Cancer Center Core Grant P30CA47904.

Supplementary material

10020_2014_2001046_MOESM1_ESM.pdf (1.2 mb)
Supplementary material, approximately 1.19 MB.

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Authors and Affiliations

  • Malabika Sen
    • 1
  • Kathleen Paul
    • 2
  • Maria L. Freilino
    • 1
  • Hua Li
    • 1
  • Changyou Li
    • 2
  • Daniel E. Johnson
    • 2
    • 4
  • Lin Wang
    • 3
  • Julie Eiseman
    • 4
    • 5
  • Jennifer R. Grandis
    • 1
    • 4
    • 6
  1. 1.Department of OtolaryngologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Departments of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  5. 5.University of Pittsburgh Cancer InstitutePittsburghUSA
  6. 6.Eye & Ear InstitutePittsburghUSA

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