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Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12

Gene Therapy volume 9, pages 64–74 (2002)Cite this article

Abstract

No satisfactory treatment of metastatic medullary thyroid carcinoma (MTC) is available. Cell-specific gene therapy offers a new approach. We have constructed a recombinant replication-defective adenoviral vector expressing murine interleukin-12 (mIL-12), driven by a modified CALC-I promoter (TCP). This vector (AdTCPmIL-12) includes two separate cassettes encoding mIL-12 p35 or p40 subunit controlled by TCP inserted in the E1 region of adenovirus type 5. In vitro and in vivo reporter gene expression using TCP revealed its cell-specific activity. AdTCPmIL-12-infected rat MTC (rMTC) cells produced high amounts of functional mIL-12 cells in vitro, while other cell lines infected with AdTCPmIL-12 did not. AdTCPmIL-12-transduced rMTC cells completely lost their tumorigenicity in syngenic WAG/Rij rats. Direct injection of 1 × 109 plaque forming units of AdTCPmIL-12 into subcutaneous rMTC tumors in WAG/Rij rats caused tumor regression in over 60% of animals within 20 days. Rats cured of tumors did not develop tumors after re-injection of naive rMTC cells, demonstrating lasting immunity. Treatment with AdTCPmIL-12 of one tumor resulted in regression of an established tumor at a distant site. Moreover, intratumoral or intravenous injection of AdTCPmIL-12 did not induce evident toxicity. These results indicate AdTCPmIL-12 can contribute to effective and less toxic gene therapy of MTC.

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Acknowledgements

We are grateful to our colleague Masaki Takara for giving us helpful suggestions, and to Miss Myrna Zimberg for her excellent secretarial assistance. This work was supported by a Center of Excellence award from Knoll Pharmaceuticals and by the David Wiener Research Fund.

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Authors and Affiliations

  1. Department of Medicine, Thyroid Study Unit, The University of Chicago, Chicago, IL, USA

    M Yamazaki, R Zhang & LJ DeGroot

  2. Department of Pathology, The University of Chicago, Chicago, IL, USA

    FH Straus

  3. Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia

    M Messina & BG Robinson

  4. Department of Medicine, University of Sydney, Sydney, NSW, Australia

    BG Robinson

  5. Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, Japan

    K Hashizume

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Yamazaki, M., Zhang, R., Straus, F. et al. Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12. Gene Ther 9, 64–74 (2002). https://doi.org/10.1038/sj.gt.3301617

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