TRANSGENE EXPRESSION IN MALIGNANT GLIOMA USING A REPLICATION-DEFECTIVE ADENOVIRAL VECTOR CONTAINING THE EGR-1 PROMOTER - ACTIVATION BY IONIZING-RADIATION OR UPTAKE OF RADIOACTIVE IODODEOXYURIDINE

One approach to improving the specificity of gene therapy involves usi ng radiosensitive promoters to activate gene expression selectively in the radiation field. In this study, we evaluated the ability of irrad iation to regulate the transcription of a recombinant replication-defe ctive adenovirus vector, Ad.Egr-1/lacZ, containing the radiation-induc ible Egr-1 promoter driving the beta-galactosidase reporter gene in gl ioma cells. Transcripts of the Egr-1 gene in human and rat glioma cell s were induced following irradiation with as little as 2 Gy. This dose was 10-fold less than previously reported, and comparable to doses of irradiation used clinically in standard fractionated radiotherapy for brain tumors, When 9L rat gliosarcoma cells were infected with Ad.Egr -1/lacZ in vitro and exposed to 2 Gy of external beam irradiation, the re was a threefold increase in beta-galactosidase expression. Irradiat ion of intracerebral 9L tumors infected with the Ad.Egr-1/lacZ virus, using either external beam radiotherapy (2 Gy) or the thymidine analog 5-iodo-2'-deoxyuridine radiolabeled with the Auger electron emitter i odine-125 ([I-125]IdUrd), also resulted in increased beta-galactosidas e activity of the tumor cells. These results indicate that the use of viral vectors containing radiation-inducible promoters represents a no vel therapeutic approach that enables gene therapy to be spatially and temporally regulated by ionizing radiation. These findings also suppo rt a potential role for radiation-inducible promoters in the treatment of malignant brain tumors.