Radiation therapy: activation for gene transcription and the development of genetic radiotherapy-therapeutic strategies in oncology.

Radiotherapy is a widely used local and regional modality for the treatment of cancer. Despite improved methods of radiation delivery, local recurrence accounts for treatment failure in most patients. Radiosensitizers have been studied as one approach for improving the effectiveness of radiotherapy. Few agents, however, have been shown to selectively increase the anti-tumor effects of radiation. Advances in our understanding of how cells respond molecularly to ionizing radiation have provided opportunities for the development of new approaches that selectively enhance radiotherapy of tumors. Cells respond to ionizing radiation with the activation of specific early and later response genes. These findings led us to the concept that promoters from these genes could be used to drive therapeutic transgenes introduced into irradiated tumor cells. In this strategy, designated genetic radiotherapy, radiation is combined with gene therapy, another local/regional modality, to spatially and temporally control transgene expression in the irradiated field. Tumor necrosis factor-alpha (TNF-alpha) was selected as the transgenic protein for its potent anti-tumor activity and synergistic interactions with ionizing radiation. The radio-inducible elements from the early growth response-1 (EGR-1) gene promoter have been inserted upstream to a cDNA encoding TNF-alpha and integrated into a replication-defective adenovirus (Ad.EGR-TNF). Preclinical studies have shown that tumors infected with Ad.EGR-TNF respond to radiation with induction of TNF-alpha expression and substantial increases in anti-tumor activity. Importantly, local production of TNF-alpha is not associated with the limiting toxicities encountered when this cytokine was administered systemically. Based on these findings, radiation in combination with intratumoral administration of a second generation Ad.EGR-TNF (TNFerade) has completed Phase I evaluation and has entered Phase II clinical trials.