title: Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours.
abstract: Overwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts. In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success. doi:10.1038/sj.gt.3301702
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Patterson
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
authors.forename: R L
authors.initials: RL
authors.lastname: Cowen
authors.forename: M
authors.initials: M
authors.lastname: Jaffar
authors.forename: B A
authors.initials: BA
authors.lastname: Telfer
authors.forename: M
authors.initials: M
authors.lastname: Saunders
authors.forename: R
authors.initials: R
authors.lastname: Airley
authors.forename: D
authors.initials: D
authors.lastname: Honess
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: C R
authors.initials: CR
authors.lastname: Wolf
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia; D051379:Mice; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D009593:Nitroimidazoles; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; C067834:RB 6145; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D009251:NADPH-Ferrihemoprotein Reductase