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

Gene Ther. 2000 Nov;7(22):1906-14. doi: 10.1038/sj.gt.3301315.

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.

Publication types

  • Comparative Study
  • 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.

MeSH terms

  • 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

Substances

  • Oligonucleotides, Antisense
  • Transforming Growth Factor alpha