title: Photodynamic therapy-driven induction of suicide cytosine deaminase gene.
abstract: Photodynamic therapy (PDT) of tumors is associated with induction of hypoxia that results in activation of hypoxia-inducible factors (HIFs). Several observations indicate that increased HIFs transcriptional activity in tumor cells is associated with cytoprotective responses that limit cytotoxic effectiveness of PDT. Therefore, we decided to examine whether this cytoprotective mechanism could be intentionally used for designing more efficient tumor cell cytotoxicity. To this end we transfected tumor cells with a plasmid vector carrying a suicide cytosine deaminase gene driven by a promoter containing hypoxia response elements (HRE). The presence of such a genetic molecular beacon rendered tumor cells sensitive to cytotoxic effects of a non-toxic prodrug 5-fluorocytosine (5-FC). The results of this study provides a proof of concept that inducible cytoprotective mechanisms can be exploited to render tumor cells more susceptible to cytotoxic effects of prodrugs activated by products of suicide genes.
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bil
authors.forename: Pawel
authors.initials: P
authors.lastname: Wlodarski
authors.forename: Magdalena
authors.initials: M
authors.lastname: Winiarska
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Kurzaj
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Issat
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.forename: Barbara
authors.initials: B
authors.lastname: Wegiel
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics*; D005437:Flucytosine / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010778:Photochemotherapy / Q000379:methods*; D011355:Prodrugs / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000963:Antimetabolites; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase