Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth.
We report here the use of viral fusogenic membrane glycoproteins (FMGs) as a new class of therapeutic genes for the control of tumor growth. FMGs kill cells by fusing them into large multinucleated syncytia, which die by sequestration of cell nuclei and subsequent nuclear fusion by a mechanism that is nonapoptotic, as assessed by multiple criteria. Direct and bystander killing of three different FMGs were at least one log more potent than that of herpes simplex virus thymidine kinase or cytosine deaminase suicide genes. Transduction of human tumor xenografts with plasmid DNA prevented tumor outgrowth in vivo, and cytotoxicity could be regulated through transcriptional targeting. Syncytial formation is accompanied by the induction of immunostimulatory heat shock proteins, and tumor-associated FMG expression in immunocompetent animals generated specific antitumor immunity.
Bateman
A
A
Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
Bullough
F
F
Murphy
S
S
Emiliusen
L
L
Lavillette
D
D
Cosset
F L
FL
Cattaneo
R
R
Russell
S J
SJ
Vile
R G
RG
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002459:Cell Fusion / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014760:Viral Fusion Proteins / Q000235:genetics* / Q000276:immunology
D018076:DNA, Complementary; D014760:Viral Fusion Proteins; D013937:Thymidine Kinase