Antitumor activity of recombinant adenoviral vectors expressing murine IFN-alpha in mice injected with metastatic IFN-resistant tumor cells.
Recent studies have shown that gene therapy with type I interferon (IFN) in an adenovirus vector is a powerful tool to suppress the growth of human tumors transplanted in immune-deficient mice. However, in these studies the host immune-mediated effects, which may be important in mediating the long-term control of tumor growth by these cytokines, was not studied. In this paper, we evaluate the antitumor efficacy of different adenoviral vectors containing mouse IFN-alpha genes (i.e., a first-generation replication-defective vector containing IFN-alpha1 and two different second-generation vectors containing IFN-alpha2) in immunocompetent DBA/2 mice transplanted with highly metastatic Friend leukemic cells resistant in vitro to type I IFN. We found that injection of all the different adenovirus vectors containing mouse IFN-alpha( genes resulted in a marked antitumor response in mice transplanted either subcutaneously or intravenously with IFN-resistant Friend leukemic cells compared to tumor-bearing animals inoculated with a control vector. Tumor growth inhibition after injection of IFN-adenovirus vectors was associated with a prolonged presence of high IFN levels in the sera of the injected mice. Suppression of metastatic tumor growth was also observed after a single injection of the IFN--adenovirus recombinant vectors, whereas a comparable antitumor response generally required several injections of high doses of IFN. Altogether, these results demonstrate that IFN--adenoviral vectors can efficiently inhibit metastatic tumor growth by host-mediated mechanisms and suggest that adenovirus-mediated IFN-alpha gene therapy may represent an attractive alternative to the conventional clinical use of this cytokine, which generally requires multiple injections of high IFN doses for a prolonged period of time.
Santodonato
L
L
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Ferrantini
M
M
Palombo
F
F
Aurisicchio
L
L
Delmastro
P
P
La Monica
N
N
Di Marco
S
S
Ciliberto
G
G
Du
M X
MX
Taylor
M W
MW
Belardelli
F
F
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005622:Friend murine leukemia virus; D015316:Genetic Therapy; D005822:Genetic Vectors; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007763:Lac Operon / Q000502:physiology; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy*; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016019:Survival Analysis; D014162:Transfection; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha