Pulmonary adenocarcinoma-targeted gene therapy by a cancer- and tissue-specific promoter system

Fukazawa T, Maeda Y, Durbin ML, Nakai T, Matsuoka J, Tanaka H, Naomoto Y, Tanaka N
Source: Mol Cancer Ther
Publication Date: (2007)
Issue: 6(1): 244-52
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Embryonic stem cell (ES), mouse
Species: mouse
Tissue Origin: embryo
Nucleofectorâ„¢ I/II/2b
Gene therapy is one of the approaches used to treat lung cancer. The benefit of cancer gene therapy is that different types of tumors can be selectively targeted by tumor-specific expression of therapeutic genes that include an apoptosis gene to destroy the tumor. Previously, we described a promoter (TTS promoter) that we designed that is specifically targeted to lung cancer cells but not to other types of cancer or normal cells including stem cells. In this pursuit, we further characterize the specificity of the TTS promoter in four types of lung cancer cells (squamous cell lung carcinoma, pulmonary adenocarcinoma, small-cell lung carcinoma, large-cell lung carcinoma). The TTS promoter is highly active only in pulmonary adenocarcinoma cells but not in the other three types of lung cancer cells. The specificity seems to be derived from transcription factor thyroid transcription factor 1-associating cofactors that affect human surfactant protein A1 promoter activity in pulmonary adenocarcinoma. We inserted the proapoptotic gene Bcl-2-associated X protein (Bax) into the TTS promoter (TTS/Bax). The TTS/Bax selectively causes BAX expression and cell death in pulmonary adenocarcinoma but not in other cells. Cell death caused by the BAX expression was also observed in pulmonary adenocarcinoma that is resistant to the anticancer drug gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor). BAX expression and cell death can be suppressed by dexamethasone (a glucocorticoid) treatment through negative glucocorticoid elements in the TTS promoter. Here we report a drug-controllable TTS/Bax system targeting pulmonary adenocarcinoma.