title: Genetically modified macrophages expressing hypoxia regulated cytochrome P450 and P450 reductase for the treatment of cancer.
abstract: This study describes a combined gene and cell therapy based on the genetic modification of primary human macrophages, as a treatment for cancer. Here, we have utilised the tumour-infiltrating properties of macrophages as vehicles to deliver a gene encoding a prodrug-activating enzyme such as human cytochrome P450 2B6 (CYP2B6) inside tumours followed by killing the tumour cells with the prodrug cyclophosphamide (CPA). Macrophages were transduced with an adenoviral vector that expresses human cytochrome CYP2B6 via a synthetic hypoxia responsive promoter (OBHRE) and with human P450 reductase (P450R), via the CMV promoter. In the presence of CPA, these genetically modified macrophages showed increased cytotoxicity against various tumour cell lines compared to untransduced macrophages or macrophages transduced with CYP2B6 alone. In human ovarian carcinoma xenograft models, the median survival of mice treated with genetically modified macrophages plus CPA increased up to two-fold compared to the survival of mice treated with untransduced macrophages and CPA. Genetically modified autologous macrophages may be a feasible therapeutic option for the treatment of some solid tumours, such as ovarian cancer.
authors.affiliation: Oxford BioMedica (UK) Ltd., Medawar Centre, Oxford Science Park, Oxford, UK. o.kan@oxfordbiomedica.co.uk
authors.forename: On
authors.initials: O
authors.lastname: Kan
authors.forename: Debbie
authors.initials: D
authors.lastname: Day
authors.forename: Sharifah
authors.initials: S
authors.lastname: Iqball
authors.forename: Frances
authors.initials: F
authors.lastname: Burke
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Grimshaw
authors.forename: Stuart
authors.initials: S
authors.lastname: Naylor
authors.forename: Katie
authors.initials: K
authors.lastname: Binley
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D000860:Hypoxia; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase