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TGF-alpha antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo.

Abstract
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.
AuthorsS Endo, Q Zeng, N A Burke, Y He, M F Melhem, S F Watkins, M N Lango, S D Drenning, L Huang, J Rubin Grandis
JournalGene therapy (Gene Ther) Vol. 7 Issue 22 Pg. 1906-14 (Nov 2000) ISSN: 0969-7128 [Print] England
PMID11127578 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Oligonucleotides, Antisense
  • Transforming Growth Factor alpha
Topics
  • Animals
  • Apoptosis
  • Carcinoma, Squamous Cell (therapy)
  • Cell Division
  • Cell Line
  • Gene Expression
  • Genetic Therapy (methods)
  • Head and Neck Neoplasms (therapy)
  • Humans
  • Mice
  • Mice, Nude
  • Microscopy, Fluorescence
  • Neoplasms, Experimental (therapy)
  • Oligonucleotides, Antisense (administration & dosage)
  • Random Allocation
  • Transfection (methods)
  • Transforming Growth Factor alpha (genetics)
  • Xenograft Model Antitumor Assays

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