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Pre-clinical toxicity assessment of tumor-targeted interleukin-12 low-intensity electrogenetherapy

Cancer Gene Therapy volume 18, pages 265–274 (2011)Cite this article

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Abstract

This study's goal was to assess the safety of tumor-targeted interleukin-12 (ttIL-12) when administered by electrogenetherapy in C3H/HeJ mice by identifying an initial safe dose for human dose escalation schemes, toxicity target organs, markers of toxicity, and toxicity reversibility. Tumor-free mice receiving two doses of 0.45% NaCl, 1 μg ttIL-12 DNA in 0.45% NaCl or 5 μg ttIL-12 DNA in 0.45% NaCl, 10 days apart combined with low-intensity electroporation were compared with non-treatment controls over time. All mice had blood cell counts, serum chemistry profiles, plasma interleukin-12 and IFNγ determinations, necropsy and multi-organ histopathology. Mild treatment-associated changes included electroporation-associated muscle changes that resolved by 30 days; decreased total white blood cell counts and infectious disease in the 5 μg ttIL-12 group, but not in the 1 μg group, and liver changes in ttIL-12 groups that correlated with alanine transaminase levels and resolved by 30 days. Dystrophic cardiac calcification seen in older, 5 μg ttIL-12-treated mice was the only serious toxicity. Based on these results and the lack of any effect on wound healing when combined with surgery, low-intensity electrogenetherapy with ttIL-12 appears to be safe and well tolerated.

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Acknowledgements

This investigation was partially supported by the National Institutes of Health under Ruth L Kirschstein T-32 National Research Service Award and R01 grant #R01CA120895. The authors thank Michael Fons of Inovio Biomedical Corp. for supplying the Medpulser electroporator and electrodes used in this study.

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  1. Department of Comparative Biomedical Sciences, LSU School of Veterinary Medicine, Baton Rouge, LA, USA

    S D Reed

  2. Department of Pediatrics Research, UT MD Anderson Cancer Center, UT Graduate School of Biomedical Sciences, Houston, TX, USA

    S Li

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Correspondence to S Li.

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Reed, S., Li, S. Pre-clinical toxicity assessment of tumor-targeted interleukin-12 low-intensity electrogenetherapy. Cancer Gene Ther 18, 265–274 (2011). https://doi.org/10.1038/cgt.2010.77

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