title: Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy.
abstract: Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase (NTR) gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% 02 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, CA 94305-5152, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Shibata
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D001388:Aziridines / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009601:Nitroreductases / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D001388:Aziridines; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011355:Prodrugs; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C100099:tretazicar; D008156:Luciferases; D009601:Nitroreductases