Antitumor effects of epidermal growth factor receptor antisense oligonucleotides in combination with docetaxel in squamous cell carcinoma of the head and neck.
OBJECTIVE
Antisense approaches targeting the epidermal growth factor receptor (EGFR) have been demonstrated to inhibit the growth of squamous cell carcinoma of the head and neck (SCCHN). Docetaxel is an effective chemotherapeutic agent in the treatment of SCCHN. The present study was undertaken to evaluate the antitumor mechanisms of EGFR antisense (AS) oligonucleotides administered in combination with docetaxel in preclinical models of SCCHN.


METHODS
SCCHN cells lines and xenografts were treated with an EGFR AS oligonucleotide targeting region 760-779 of EGFR mRNA (GenBank accession XM_004738) alone and in combination with docetaxel. Proliferation in vitro and tumor growth in vivo were examined in addition to determinations of EGFR expression and signaling pathways to evaluate antitumor mechanisms.


RESULTS
A combination of docetaxel with EGFR AS resulted in increased cytotoxicity compared with treatment with docetaxel plus EGFR sense oligonucleotides or docetaxel alone after 24 h. Tumor volumes were significantly reduced in the mice treated with a combination of intratumoral EGFR AS and systemic docetaxel compared with mice receiving monotherapy. The combination of docetaxel plus EGFR AS resulted in decreased expression levels of EGFR, phosphotyrosine signal transducers and activators of transcription 3, vascular endothelial growth factor, and pAKT compared with expression levels after either treatment alone.


CONCLUSIONS
A combination of EGFR AS and docetaxel may be effective in the treatment of SCCHN with a reduced toxicity profile compared with standard chemotherapy regimens.
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Hideo
H
Niwa
Abbey L
AL
Wentzel
Mengfeng
M
Li
William E
WE
Gooding
Vivian Wai Yan
VW
Lui
Jennifer Rubin
JR
Grandis
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019000:Phosphotyrosine / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D043823:Taxoids; D013778:Tetrazolium Salts; D013844:Thiazoles; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D019000:Phosphotyrosine; D066246:ErbB Receptors; C022616:thiazolyl blue