title: Gene therapy approaches to enhance bioreductive drug treatment.
abstract: Hypoxia, or a lack of oxygen, occurs in 50-60% of solid human tumours. Clinical studies have shown that the presence and extent of hypoxia in a tumour cannot be predicted by size or histopathological stage but it is predictive of a poor outcome following radiotherapy, chemotherapy and surgery. However, as a physiological feature of tumours, it can be exploited and researchers have developed many hypoxia-selective chemotherapies or bioreductive drugs that are in varying stages of clinical development. These agents are prodrugs that have two key requirements for their biological activation: they require the reductive environment of a hypoxic tumour cell and the appropriate complement of cellular reductase enzymes. To overcome tumour heterogeneity in reductase enzyme levels and enhance bioreductive drug metabolism a gene therapy strategy can be employed. We have reviewed this field and also present our own pre-clinical research using gene therapy to enhance bioreductive drug treatment for the treatment of cancer. We have specifically focused on studies enhancing lead clinical bioreductive drugs. We consider the metabolic requirements for their activation and we highlight the key in vivo studies supporting the future clinical development of hypoxia-targeted gene-directed enzyme prodrug therapy.
authors.affiliation: Department of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Rd, Manchester M13 9PT, UK. Rachel.cowen@manchester.ac.uk
authors.forename: R L
authors.initials: RL
authors.lastname: Cowen
authors.forename: E J
authors.initials: EJ
authors.lastname: Garside
authors.forename: B
authors.initials: B
authors.lastname: Fitzpatrick
authors.forename: M V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
mesh_terms: D000477:Alkylating Agents / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000880:Anthraquinones; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000627:therapeutic use; D003580:Cytochromes / Q000378:metabolism / Q000627:therapeutic use; D015786:Cytochromes b5 / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D016685:Mitomycin / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000627:therapeutic use; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D014969:Xanthine Oxidase / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000477:Alkylating Agents; D000880:Anthraquinones; D003580:Cytochromes; D051793:Hypoxia-Inducible Factor 1; D011355:Prodrugs; D016685:Mitomycin; C094428:AQ4N; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase