Reduction of liver metastasis of intraocular melanoma by interferon-beta gene transfer.
OBJECTIVE
This study determined whether adenovirus-mediated transfer of the murine interferon-beta (AdCMVIFN-beta) gene protects against liver metastases arising from intraocular melanomas in mice.


METHODS
A replication-deficient adenovirus vector (AdCMVIFN-beta) was used for the in vivo transfer of the murine IFN-beta gene into intraocular melanoma-bearing mice. AdCMVIFN-beta was injected either intravenously or directly into the intraocular melanomas. The effect of gene transfer on liver metastases was ascertained by histopathologic analysis of the livers and by measuring serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are two enzymes associated with liver metastases in patients with uveal melanoma.


RESULTS
Mice treated with two intratumoral injections of AdCMVIFN-beta had a 68% reduction in metastatic liver lesions (P = 0.016) and a 51% reduction in liver enzyme levels compared with control mice (P = 0.02). However, the antimetastatic effect of AdCMVIFN-beta was not directly attributable to the adenovirus vector or virus-mediated cytolysis of tumor cells. Intravenous treatment with AdCMVIFN-beta resulted in an 86% reduction in the number of metastatic foci in the liver (P = 0.014) and a 61% reduction of serum AST levels compared with mice treated with AdCMVLacZ (P = 0.015). AdCMVIFN-beta treatment produced a sharp increase in the NK cell activity that was demonstrable in vivo and in vivo. In vivo depletion of NK cells by anti-asialo GM1 antibody abrogated the antimetastatic effects of AdCMVIFN-beta.


CONCLUSIONS
The results support the feasibility of activation of NK cell function through gene transfer as one possible therapeutic strategy for reducing hepatic metastases of uveal melanomas.
Alizadeh
Hassan
H
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9057, USA.
Howard
Kevin
K
Mellon
Jessee
J
Mayhew
Elizabeth
E
Rusciano
Dario
D
Niederkorn
Jerry Y
JY
D000256:Adenoviridae / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents; D001219:Aspartate Aminotransferases / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005677:G(M1) Ganglioside / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000556:secondary* / Q000628:therapy*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D000970:Antineoplastic Agents; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D016899:Interferon-beta; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase