Photodynamic therapy-driven induction of suicide cytosine deaminase gene

Bil, Jacek; Wlodarski, Pawel; Winiarska, Magdalena; Kurzaj, Zuzanna; Issat, Tadeusz; Jozkowicz, Alicja; Wegiel, Barbara; Dulak, Jozef; Golab, Jakub

doi:10.1016/j.canlet.2009.09.012

« Previous Next »Cancer Letters
Volume 290, Issue 2 , Pages 216-222, 28 April 2010

Photodynamic therapy-driven induction of suicide cytosine deaminase gene

Jacek Bil
- Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 02-097 Warsaw, Poland
Pawel Wlodarski
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland
Magdalena Winiarska
- Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 02-097 Warsaw, Poland
Zuzanna Kurzaj
- Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 02-097 Warsaw, Poland
Tadeusz Issat
- Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 02-097 Warsaw, Poland
Alicja Jozkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
Barbara Wegiel
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
Jozef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
Jakub Golab
- Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 02-097 Warsaw, Poland
- Institute of Physical Chemistry, Polish Academy of Sciences, Department 3, 01-224 Warsaw, Poland
- Corresponding author. Address: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 1A Banacha Str., F Building, 02-097 Warsaw, Poland. Tel.: +48 22 5992199; fax: +48 22 5992194.

Received 1 July 2009; received in revised form 16 September 2009; accepted 17 September 2009. published online 12 October 2009.

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.

Keywords: Photodynamic therapy, Cytosine deaminase, 5-Fluorocytosine, Suicide gene therapy, Cancer