Antitumor effect of antibiotic resistance gene-free plasmids encoding interleukin-12 in canine melanoma model.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9432230 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5500 (Electronic) Linking ISSN: 09291903 NLM ISO Abbreviation: Cancer Gene Ther Subsets: MEDLINE
    • Publication Information:
      Publication: <2002->: London : Nature Publishing Group
      Original Publication: Norwalk, CT : Appleton & Lange, c1994-
    • Subject Terms:
      Drug Resistance, Microbial* ; Interleukin-12*/biosynthesis ; Interleukin-12*/genetics ; Melanoma*/genetics ; Melanoma*/metabolism ; Melanoma*/pathology ; Melanoma*/therapy ; Plasmids*/genetics ; Plasmids*/pharmacology; Genetic Therapy/*methods; Animals ; Cell Line, Tumor ; Dogs ; Female ; Gene Transfer Techniques ; Humans ; Mice ; Mice, Nude ; Xenograft Model Antitumor Assays
    • Abstract:
      The electrotransfer of interleukin-12 (IL-12) has been demonstrated as an efficient and safe treatment for tumors in veterinary oncology. However, the plasmids used encode human or feline IL-12 and harbor the gene for antibiotic resistance. Therefore, our aim was to construct plasmids encoding canine IL-12 without the antibiotic resistance genes driven by two different promoters: constitutive and fibroblast-specific. The results obtained in vitro in different cell lines showed that following gene electrotransfer, the newly constructed plasmids had cytotoxicity and expression profiles comparable to plasmids with antibiotic resistance genes. Additionally, in vivo studies showed a statistically significant prolonged tumor growth delay of CMeC-1 tumors compared to control vehicle-treated mice after intratumoral gene electrotransfer. Besides the higher gene expression obtained by plasmids with constitutive promoters, the main difference between both plasmids was in the distribution of the transgene expression. Namely, after gene electrotransfer, plasmids with constitutive promoters showed an increase of serum IL-12, whereas the gene expression of IL-12, encoded by plasmids with fibroblast-specific promoters, was restricted to the tumor. Furthermore, after the gene electrotransfer of plasmids with constitutive promoters, granzyme B-positive cells were detected in the tumor and spleen, indicating a systemic effect of the therapy. Therefore, plasmids with different promoters present valuable tools for focused therapy with local or systemic effects. The results of the present study demonstrated that plasmids encoding canine IL-12 under constitutive and fibroblast-specific promoters without the gene for antibiotic resistance provide feasible tools for controlled gene delivery that could be used for the treatment of client-owned dogs.
    • Accession Number:
      187348-17-0 (Interleukin-12)
    • Publication Date:
      Date Created: 20180330 Date Completed: 20190620 Latest Revision: 20190620
    • Publication Date:
      20240829
    • Accession Number:
      10.1038/s41417-018-0014-5
    • Accession Number:
      29593358