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Photodynamic Therapy-mediated Oxidative Stress as a Molecular Switch for the Temporal Expression of Genes Ligated to the Human Heat Shock Promoter¹

Clayton Center for Ocular Oncology [M. C. L., A. F., S. W., A. M. R. F., C. J. G.], Children’s Hospital Los Angeles; and Departments of Pediatrics [C. J. G.], Radiation Oncology [C. J. G.], and Molecular Pharmacology and Toxicology [C. J. G.], University of Southern California, Los Angeles, California 90027

Oxidative stress associated with photodynamic therapy (PDT) is a transcriptional inducer of genes encoding stress proteins, including those belonging to the heat shock protein (hsp) family. The efficiency of PDT to function as a molecular switch by initiating expression of heterologous genes ligated to the human hsp promoter was examined in the present study. Selective and temporal reporter gene expression was documented after PDT in mouse radiation-induced fibrosarcoma cells stably transfected with recombinant vectors containing an hsp promoter ligated to either the lac-z or CAT reporter genes and in transfected radiation-induced fibrosarcoma tumors grown in C3H mice. Hyperthermia treatments were included as a positive control for all experiments. Expression vectors containing either human p53 or tumor necrosis factor (TNF)- cDNA under the control of an hsp promoter were also constructed and evaluated. A p53 null and TNF--resistant human ovarian carcinoma (SKOV-3) cell line was stably transfected with either the p53 or TNF- constructs. Inducible expression and function of p53 as well as inducible expression, secretion, and biological activity of TNF- were documented after PDT or hyperthermia in transfected SKOV cells. These results demonstrate that PDT-mediated oxidative stress can function as a molecular switch for the selective and temporal expression of heterologous genes in tumor cells containing expression vectors under the control of an hsp promoter.

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