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.
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.
Asselin-Paturel
C
C
U487 INSERM, Institut Gustave-Roussy, Villejuif, France.
Lassau
N
N
Guinebretière
J M
JM
Zhang
J
J
Gay
F
F
Bex
F
F
Hallez
S
S
Leclere
J
J
Peronneau
P
P
Mami-Chouaib
F
F
Chouaib
S
S
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
D018664:Interleukin-12