Cytotoxicity and antiangiogenesis by fibroblast growth factor 2-targeted Ad-TK cancer gene therapy.
OBJECTIVE
Human head and neck squamous cell carcinoma (HNSCC) in addition to lung, skin, ovarian, and other cancers overexpress fibroblast growth factor (FGF) receptors on both individual tumor cells and endothelial cells within the tumor microenvironment. The purpose of this study was to investigate whether FGF2-targeted gene therapy could redirect adenoviral vectors encoding the herpes simplex virus thymidine kinase gene (Ad-TK) to FGF receptors on tumor and endothelial cells with the intent of improving both the efficiency of transgene expression and the antitumor response.


METHODS
An Ad-TK vector consisting of a conjugate of FGF2 linked to a Fab' fragment against the adenoviral knob region was directly delivered to human HNSCC xenograft tumors in nude mice, which were subsequently dosed with ganciclovir. Tumor specimens were assessed for herpes simplex virus thymidine kinase (HSV-tk) transgene mRNA expression, FGF1/2 receptor expression, terminal deoxynucleotidyl transferase biotin-deoxy uridine triphosphate nick end labeling assay for apoptosis, CD31 immunohistochemistry to estimate tumor microvessel density, and tumor volume change.


RESULTS
FGF2-retargeted Ad-TK gene therapy demonstrated significant increases in both HSV-tk mRNA expression and cellular apoptosis levels, and a significant decrease in tumor volume size compared with all other groups. Furthermore, microvessel density was significantly lower in the FGF2-retargeted Ad-TK group, indicating a strong antiangiogenesis effect.


CONCLUSIONS
These data suggest that FGF2-retargeted Ad-TK produces a combination of expected direct antitumor cytotoxicity and a newly reported antiangiogenesis effect that could prove promising as a novel therapeutic approach in the treatment of FGF receptor-expressing cancers.
Saito
Koichiro
K
Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Khan
Khurram
K
Sosnowski
Barbara
B
Li
Daqing
D
O'Malley
Bert W
BW
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000493:pharmacokinetics; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000150:complications / Q000235:genetics / Q000628:therapy; D011897:Random Allocation; D011994:Recombinant Proteins; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014018:Tissue Distribution; D019076:Transgenes / Q000235:genetics
D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D013937:Thymidine Kinase