Enhancing tumor radiosensitivity by intracellular delivery of survivin antagonists

Radiotherapy is frequently applied to control local tumors by mechanisms of direct killing tumor cells and inducing tumor vascular endothelial cells apoptosis. Recently, it has been demonstrated that survivin, an intracellular molecule with anti-apoptotic function, is widely expressed in human malignancies and its expression correlates with radioresistance in several tumors. Moreover, VEGF, which is highly expressed in solid tumors and further up-regulated by irradiation, has been shown to induce survivin expression in both tumor cells and vascular endothelial cells. Thus provide a survival signal to these cells and induce radioresistance to the subsequent irradiation exposure. Knocking down the expression of survivin by RNA interference or transfecting with a gene coding for a dominant negative survivin has been proved to be efficient in enhancing tumor cell radiosensitivity and improving tumor response to radiotherapy. The development of protein transduction technology made it possible to deliver large molecules into mammalian cells. We postulate that dominant negative mutants of survivin could fuse with protein transduction domain and the fusion proteins could cross cellular membranes and generate their biological activity to serve as tumor radiosensilizers. If the hypothesis proved to be practical, it would provide us an alternate method to enhance tumor radiosensitivity and the fusion proteins would be widely applicated in clinical settings because they were safer than gene therapy.