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Transfer of the murine interleukin-12 gene in vivo by a Semliki Forest virus vector induces B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography

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Abstract

To elucidate further the potential of a Semliki Forest virus (SFV) vector in vivo for gene therapy, we constructed a vector, SFV-IL12, to transfer murine IL-12 genes into tumors. A single intratumoral injection of established B16 murine melanoma with SFV-IL12 resulted in a significant inhibition of tumor growth, while injection with SFV-LacZ had no effect. This antitumoral activity correlated with an increase of IFNγ production, MIG and IP-10 mRNA expression, both at the tumor site and at the periphery. In contrast, no increase in CTL- or NK cell-mediated cytotoxic response could be detected, ruling out the involvement of T and NK cell cytotoxicity. To determine how the transfer of IL-12 genes induced tumor regression, the antiangiogenicactivity of SFV-IL12 was investigated using Doppler ultrasonography (DUS). SFV-IL12 inhibited in situ neovascularization within the tumor, without affecting the resistance index of pre-existing intratumoral blood flows. In addition, histological analysis of SFV-IL12-treated tumors showed massive tumor necrosis induced by SFV-IL12 treatment. These data indicate that SFV-IL12 inhibits tumor growth through its antiangiogenic activity, demonstrated for the first time in vivo by DUS, and suggest that the SFV vector may be a novel valuable tool in tumor gene transfer.

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Authors and Affiliations

  1. U487 INSERM, Institut Gustave-Roussy, Villejuif, France

    C Asselin-Paturel, N Lassau, F Gay, F Mami-Chouaib & S Chouaib

  2. Département d’Imagerie Médicale, Institut Gustave-Roussy, Villejuif, France

    N Lassau & J Leclere

  3. Département d’Anatomo-Pathologie, Institut Gustave-Roussy, Villejuif, France

    J-M Guinebretière

  4. Département de Biologie Moleculaire, Université Libre de Bruxelles, Belgium

    J Zhang, F Bex & S Hallez

  5. CNRS ESA 70.57, Université de Jussieu, Paris, France

    P Peronneau

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  1. C Asselin-Paturel
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  2. N Lassau
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  10. F Mami-Chouaib
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Asselin-Paturel, C., Lassau, N., Guinebretière, JM. et al. Transfer of the murine interleukin-12 gene in vivo by a Semliki Forest virus vector induces B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography. Gene Ther 6, 606–615 (1999). https://doi.org/10.1038/sj.gt.3300841

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  • DOI: https://doi.org/10.1038/sj.gt.3300841

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