title: 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.
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 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.
authors.affiliation: U487 INSERM, Institut Gustave-Roussy, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Asselin-Paturel
authors.forename: N
authors.initials: N
authors.lastname: Lassau
authors.forename: J M
authors.initials: JM
authors.lastname: Guinebretière
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Gay
authors.forename: F
authors.initials: F
authors.lastname: Bex
authors.forename: S
authors.initials: S
authors.lastname: Hallez
authors.forename: J
authors.initials: J
authors.lastname: Leclere
authors.forename: P
authors.initials: P
authors.lastname: Peronneau
authors.forename: F
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: S
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D000818:Animals; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D018664:Interleukin-12 / Q000235:genetics*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000000981:diagnostic imaging / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012672:Semliki forest virus / Q000235:genetics*; D013047:Specific Pathogen-Free Organisms; D018608:Ultrasonography, Doppler
chemical_list: D018664:Interleukin-12