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

Unlike normal mucosal squamous epithelial cells, head and neck squamous cel l carcinomas (HNSCCs) overexpress TGF-alpha mRNA and protein which is requi red to sustain the proliferation of HNSCC cells in vitro. To determine whet her TGF-alpha expression contributes to tumor growth in vivo, cationic lipo some-mediated gene transfer was used to deliver an antisense expression con struct targeting the human TGF-alpha gene into human head and neck tumor ce lls, grown as subcutaneous xenografts in nude mice. The TGF-alpha antisense gene was immediately detected in the cytoplasm of the tumor cells, translo cated to the nucleus by 12 h and remained localized to the nucleus for up t o 3 days. Direct inoculation of the TGF-alpha antisense (but not the corres ponding sense) construct into established HNSCC tumors resulted in inhibiti on of tumor growth. Sustained antitumor effects were observed for up to 1 y ear after the treatments were discontinued. Down-modulation of TGF-alpha wa s accompanied by increased apoptosis in vivo. These experiments indicate th at interference with the TGF-alpha /EGFR autocrine signaling pathway may be an effective therapeutic strategy for cancers which overexpress this ligan d/receptor pair.