title: Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment.
abstract: Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FIN-70210 Kuopio, Finland.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Leinonen
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Ruotsalainen
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Määttä
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Laitinen
authors.forename: Suvi M
authors.initials: SM
authors.lastname: Kuosmanen
authors.forename: Emilia
authors.initials: E
authors.lastname: Kansanen
authors.forename: Jere T
authors.initials: JT
authors.lastname: Pikkarainen
authors.forename: Jari P
authors.initials: JP
authors.lastname: Lappalainen
authors.forename: Haritha
authors.initials: H
authors.lastname: Samaranayake
authors.forename: Hanna P
authors.initials: HP
authors.lastname: Lesch
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D061745:Antioxidant Response Elements; D045744:Cell Line, Tumor; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013937:Thymidine Kinase; D015774:Ganciclovir