This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fukazawa, T. Articles by Tanaka, N. Search for Related Content PubMed PubMed Citation Articles by Fukazawa, T. Articles by Tanaka, N.

Research Articles: Therapeutics, Targets, and Development

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

¹ First Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; ² Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; ³ Department of Ecology and Evolutionary Biology, University of California, Irvine, California; and ⁴ Division of Clinical Immunology and Department of Rheumatology and Allergy, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Requests for reprints: Takuya Fukazawa, First Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7257; Fax: 81-86-221-8775. E-mail: FukazawaT{at}aol.com

Abstract

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. [Mol Cancer Ther 2007;6(1):244–52]

Grant support: Ministry of Education, Science, and Culture and Ministry of Health and Welfare, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/14/06; revised 9/19/06; accepted 11/10/06.