Pulmonary adenocarcinoma-targeted gene therapy by a cancer- and tissue-specific promoter system.
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.
Fukazawa
Takuya
T
First Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. FukazawaT@aol.com
Maeda
Yutaka
Y
Durbin
Mary L
ML
Nakai
Toru
T
Matsuoka
Junji
J
Tanaka
Hirotoshi
H
Naomoto
Yoshio
Y
Tanaka
Noriaki
N
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000256:Adenoviridae; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics*; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D037662:Pulmonary Surfactant-Associated Protein A; D012333:RNA, Messenger; C445842:SFTPA1 protein, human; C504003:TTF1 protein, human; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D003907:Dexamethasone