TGF-alpha antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo.
Unlike normal mucosal squamous epithelial cells, head and neck squamous cell carcinomas (HNSCCs) overexpress TGF-alpha mRNA and protein which is required to sustain the proliferation of HNSCC cells in vitro. To determine whether TGF-alpha expression contributes to tumor growth in vivo, cationic liposome-mediated gene transfer was used to deliver an antisense expression construct targeting the human TGF-alpha gene into human head and neck tumor cells, grown as subcutaneous xenografts in nude mice. The TGF-alpha antisense gene was immediately detected in the cytoplasm of the tumor cells, translocated to the nucleus by 12 h and remained localized to the nucleus for up to 3 days. Direct inoculation of the TGF-alpha antisense (but not the corresponding sense) construct into established HNSCC tumors resulted in inhibition of tumor growth. Sustained antitumor effects were observed for up to 1 year after the treatments were discontinued. Down-modulation of TGF-alpha was accompanied by increased apoptosis in vivo. These experiments indicate that interference with the TGF-alpha/EGFR autocrine signaling pathway may be an effective therapeutic strategy for cancers which overexpress this ligand/receptor pair.
Endo
S
S
Department of Otolaryngology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, PA 15213, USA.
Zeng
Q
Q
Burke
N A
NA
He
Y
Y
Melhem
M F
MF
Watkins
S F
SF
Lango
M N
MN
Drenning
S D
SD
Huang
L
L
Rubin Grandis
J
J
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D002455:Cell Division; D002460:Cell Line; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009374:Neoplasms, Experimental / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D011897:Random Allocation; D014162:Transfection / Q000379:methods*; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D016376:Oligonucleotides, Antisense; D016211:Transforming Growth Factor alpha