title: Enhanced photodynamic therapy efficacy with inducible suicide gene therapy controlled by the grp promoter.
abstract: Photodynamic therapy (PDT) is a promising cancer treatment involving the administration of a tumor-localizing photosensitizer followed by the photochemical generation of cytotoxic singlet oxygen. PDT elicits strong transcriptional activation of a variety of genes including stress response genes belonging to the glucose-regulated protein (grp) family. Oxidative stress and hypoxia can activate GRP-78, and both of these physiological insults occur in treated tissue during and/or after PDT. In the current study, we evaluated the grp promoter as a PDT-inducible molecular switch for controlled expression of the herpes simplex virus-thymidine kinase (HSV-tk) suicide gene in mouse mammary adenocarcinoma (TSA) cells and tumors stably transduced with the G1NaGrpTk retroviral expression vector. We also examined whether PDT-inducible expression of HSV-tk, together with systemic administration of ganciclovir, could enhance the tumoricidal responsiveness of PDT. Inducible expression of HSV-tk was observed after PDT in stably transduced TSA cells grown in culture and in TSA tumors growing in BALB/c mice. We also observed enhanced tumoricidal activity in mice with TSA tumors containing the G1NaGrpTk expression vector treated with PDT plus ganciclovir when compared with either treatment alone. Our results confirm that the grp promoter was able to effectively function as a molecular switch for the inducible expression of the HSV-tk gene after exposure to PDT.
authors.affiliation: Clayton Center for Ocular Oncology, Childrens Hospital Los Angeles, California 90027, USA.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Luna
authors.forename: Xinke
authors.initials: X
authors.lastname: Chen
authors.forename: Sam
authors.initials: S
authors.lastname: Wong
authors.forename: Janet
authors.initials: J
authors.lastname: Tsui
authors.forename: Natalie
authors.initials: N
authors.lastname: Rucker
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gomer
mesh_terms: D000818:Animals; D015774:Ganciclovir / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D010778:Photochemotherapy / Q000379:methods*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; C018551:glucose-regulated proteins; D013937:Thymidine Kinase; D015774:Ganciclovir