Photodynamic therapy-driven induction of suicide cytosine deaminase gene.
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.
Bil
Jacek
J
Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Poland.
Wlodarski
Pawel
P
Winiarska
Magdalena
M
Kurzaj
Zuzanna
Z
Issat
Tadeusz
T
Jozkowicz
Alicja
A
Wegiel
Barbara
B
Dulak
Jozef
J
Golab
Jakub
J
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
D000963:Antimetabolites; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase