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

• Published in: Gene therapy Vol. 6; no. 4; pp. 606 - 615
• Main Authors: ASSELIN-PATUREL, C, LASSAU, N, CHOUAIB, S, GUINEBRETIERE, J.-M, ZHANG, J, GAY, F, BEX, F, HALLEZ, S, LECLERE, J, PERONNEAU, P, MAMI-CHOUAIB, F
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.04.1999
• Subjects: Animals; Biological and medical sciences; Biotechnology; Cytotoxicity; Doppler effect; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Gene Transfer Techniques; Genes; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Injection; Interleukin 1; Interleukin 12; Interleukin-12 - genetics; IP-10 protein; Lymphocytes T; Melanoma; Melanoma, Experimental - blood supply; Melanoma, Experimental - diagnostic imaging; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Mice, Nude; Natural killer cells; Neovascularization, Pathologic - therapy; Reverse Transcriptase Polymerase Chain Reaction; Semliki Forest virus; Semliki forest virus - genetics; Specific Pathogen-Free Organisms; Tumors; Ultrasonic imaging; Ultrasonography, Doppler; Vascularization; γ-Interferon; Antineoplastic agent; Semliki forest virus; Cytokine; Rodentia; Togaviridae; Interleukin 12; Gene expression; Genetic transfer; Virus; Angiogenesis; In vivo; Vertebrata; Mammalia; Gene; Mouse; Immunotherapy; Alphavirus; Tumor; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3300841

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 IFN gamma 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 to IL-12 genes induced tumor regression, the antiangiogenic-activity 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.