Cancer Therapy
Drug-regulatable cancer cell death induced by BID under control of the tissue-specific, lung cancer-targeted TTS promoter system
Takuya Fukazawa,
Yutaka Maeda,
Junji Matsuoka,
Noriaki Tanaka,
Hirotoshi Tanaka,
Mary L. Durbin,
Yoshio Naomoto,
Corresponding Author
Takuya Fukazawa
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, JapanSearch for more papers by this authorYutaka Maeda
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorJunji Matsuoka
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorNoriaki Tanaka
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorHirotoshi Tanaka
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Search for more papers by this authorMary L. Durbin
Department of Ecology and Evolutionary Biology, University of California, Irvine, CA
Search for more papers by this authorYoshio Naomoto
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorTakuya Fukazawa,
Yutaka Maeda,
Junji Matsuoka,
Noriaki Tanaka,
Hirotoshi Tanaka,
Mary L. Durbin,
Yoshio Naomoto,
Corresponding Author
Takuya Fukazawa
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, JapanSearch for more papers by this authorYutaka Maeda
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorJunji Matsuoka
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorNoriaki Tanaka
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorHirotoshi Tanaka
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Search for more papers by this authorMary L. Durbin
Department of Ecology and Evolutionary Biology, University of California, Irvine, CA
Search for more papers by this authorYoshio Naomoto
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Search for more papers by this authorAbstract
Gene therapy and virotherapy are among the approaches currently being used to treat lung cancer. The success of cancer gene therapy depends on treatments where different types of tumors can be selectively targeted and destroyed without affecting normal cells and tissue. Previously, we described a promoter system (TTS) that we designed that is specifically targeted to lung cancer cells but which does not affect other types of cells including stem cells. In our study, we have enhanced the utility of the TTS system by inserting the pro-apoptotic gene BH3 domain interacting death agonist (Bid) into the TTS promoter system (TTS/Bid) to create a drug regulatable lung cancer-specific gene therapy. A recombinant adenoviral vector was used to introduce TTS/Bid (Ad-TTS/Bid) into lung cancer cells. BID expression and apoptosis occurred in A549 pulmonary adenocarcinoma cells but little Bid expression or apoptosis occurred in MCF7 breast cancer cells or in normal human lung fibroblasts. The use of cisplatin enhanced the processing of full length BID to t-BID which significantly increased lung cancer-specific cell death. In in vivo experiments, intraperitonal injection of cisplatin enhanced the antitumor effects of the vector in a lung cancer xeno-graft mouse model. Moreover, dexamethasone effectively suppressed exogenous BID expression and the antitumor effect of Ad-TTS/Bid both in vitro and in vivo. Here, we describe the efficacy of the use of cisplatin and dexamethasone with the anti lung cancer promoter system (Ad-TTS/Bid) for a safe and effective gene therapy against advanced lung cancer. © 2009 UICC
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