Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter.
BACKGROUND
Squamous cell carcinomas of the head and neck (SCCHN), unlike normal mucosal squamous epithelial cells, overexpress epidermal growth factor receptor (EGFR) messenger RNA and protein. EGFR protein is required to sustain the proliferation of SCCHN cells in vitro. To determine whether EGFR expression contributes to tumor growth, we investigated the effect of suppressing EGFR expression in tumor xenografts through in situ expression of antisense oligonucleotides.


METHODS
Intratumoral cationic liposome-mediated gene transfer was used to deliver plasmids capable of expressing sense or antisense EGFR sequences into human head and neck tumors, which were grown as subcutaneous xenografts in nude mice. The oligonucleotides were expressed under the control of the U6 RNA promoter.


RESULTS
Direct inoculation of the EGFR antisense (but not the corresponding sense) plasmid construct into established SCCHN xenografts resulted in inhibition of tumor growth, suppression of EGFR protein expression, and an increased rate of apoptosis (programmed cell death). Sustained antitumor effects were observed for up to 2 weeks after the treatments were discontinued.


CONCLUSIONS
These results suggest that interference with EGFR expression, using an antisense-based gene therapy approach, may be an effective means of treating EGFR-overexpressing tumors, including SCCHN.
Department of Pharmacology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, PA, USA.
Y
Y
He
Q
Q
Zeng
S D
SD
Drenning
M F
MF
Melhem
D J
DJ
Tweardy
L
L
Huang
J R
JR
Grandis
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016372:RNA, Antisense / Q000235:genetics* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D012194:RNA-Directed DNA Polymerase; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics; D014158:Transcription, Genetic
D016372:RNA, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D066246:ErbB Receptors; D012194:RNA-Directed DNA Polymerase