title: Investigation of alternative prodrugs for use with E. coli nitroreductase in 'suicide gene' approaches to cancer therapy.
abstract: The most commonly employed 'suicide' gene/prodrug system used in cancer gene therapy is the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir system. We have examined the efficacy of an alternative approach utilising the E. coli nitroreductase B enzyme with CB1954 and a variety of other prodrugs. V79 cells transfected with a nitroreductase expression vector were up to 770-fold more sensitive to CB1954 than control non-expressing cells. In general other prodrugs which were found by HPLC to act as substrates for purified E. coli nitroreductase also exhibited increased cytotoxicity against the nitroreductase-expressing cells, although this correlation was not absolute. In particular nitrofurazone (97-fold) and additional aromatic nitro-compounds (nine- to 50-fold) showed a large differential whereas the quinones and the antimetabolite, B-FU, were less effective (< three-fold). The results support the possibility of using nitroreductase and CB1954 for 'suicide gene' therapy and in addition suggest that alternative prodrugs, such as nitrofurazone, warrant further investigation in this novel approach.
authors.affiliation: Richard Dimbleby Department of Cancer Research, Rayne Institute, St Thomas' Hospital, London, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Bailey
authors.forename: R J
authors.initials: RJ
authors.lastname: Knox
authors.forename: S M
authors.initials: SM
authors.lastname: Hobbs
authors.forename: T C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: A B
authors.initials: AB
authors.lastname: Mauger
authors.forename: R G
authors.initials: RG
authors.lastname: Melton
authors.forename: P J
authors.initials: PJ
authors.lastname: Burke
authors.forename: T A
authors.initials: TA
authors.lastname: Connors
authors.forename: I R
authors.initials: IR
authors.lastname: Hart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001388:Aziridines / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002384:Catalysis; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli / Q000201:enzymology*; D015316:Genetic Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D009601:Nitroreductases / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; D009601:Nitroreductases