title: Enhanced antiangiogenic therapy of squamous cell carcinoma by combined endostatin and epidermal growth factor receptor-antisense therapy.
abstract: OBJECTIVE
  We tested the combined effects of antiangiogenic endostatin and epidermal growth factor receptor (EGFR) antisense gene therapy on squamous cell carcinoma (SCC).
  
  
  RESULTS
  The 1483 cell line of human head and neck SCC (HNSCC) and SCC-VII/SF murine SCC cells was used to establish tumors in nude mice and immunocompetent C3H mice, respectively. Tumor-bearing mice were treated with endostatin (20 mg/kg/day, s.c.), liposomal EGFR-antisense expression plasmid (25 microg/mouse, three times/week, intratumoral), a combination of both agents, or liposomal EGFR-sense plasmid as a control. Endostatin or EGFR-antisense alone significantly, yet partially, inhibited the growth of 1483 and SCC-VII/SF tumors, and a combination of both treatments completely blocked tumor growth. Immunohistochemistry analysis demonstrated that a complete suppression of tumor angiogenesis was achieved by the combination treatment. Down-regulation of vascular endothelial growth factor was shown in EGFR-antisense-treated tumors. These results suggest that the EGFR-antisense treatment, in addition to its inhibitory activity on tumor cell proliferation, might have a synergistic effect with endostatin on SCC-induced angiogenesis. In vitro studies demonstrated that EGFR inhibition by antisense oligonucleotides or EGFR-specific tyrosine kinase inhibitor down-regulated the production of VEGF in HNSCC cells. Additional experiments demonstrated that these EGFR inhibition approaches also directly suppressed the growth of endothelial cells.
  
  
  CONCLUSIONS
  A combination of endostatin and EGFR targeting strategies profoundly inhibited the angiogenesis and growth of SCC in vivo. EGFR-antisense therapy might have multiple inhibitory effects against both tumor cells and endothelial cells, leading to enhanced antitumor efficacy. Such a combination strategy might represent a novel and promising approach for HNSCC therapy.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA. mengfeng@pitt.edu
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Caisheng
authors.initials: C
authors.lastname: Ye
authors.forename: Chong
authors.initials: C
authors.lastname: Feng
authors.forename: Frank
authors.initials: F
authors.lastname: Riedel
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Zeng
authors.forename: Jennifer Rubin
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000628:therapy*; D002455:Cell Division; D002478:Cells, Cultured; D003094:Collagen / Q000627:therapeutic use*; D015536:Down-Regulation; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010446:Peptide Fragments / Q000627:therapeutic use*; D010957:Plasmids / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D043169:Endostatins; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D011799:Quinazolines; D011994:Recombinant Proteins; D003094:Collagen; D066246:ErbB Receptors; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline