New targets for tumor radiosensitization

Abstract

Targeting of radiotherapy to cancer cells and avoiding irradiation of normal tissue plays a central role in improving the efficacy of radiotherapy. Biological targeting requires a systemically given compound that interacts with radiation. The degree of targeting is critically dependent on the specificity of the metabolic process used. Over the last few years, there has been an explosion in the understanding of cellular, biochemical and molecular effects of ionizing radiation in eukaryotic cells. Many of the genes encoding proteins involved in repairing radiation damage have been identified and cloned. These proteins are potential products for modifying the radiation response of normal and malignant tissues. Although our knowledge of these signaling pathways is quite rudimentary, we can now begin to explore how some of these tumor genes or protein products may be targets for modifying the ionizing radiation response in human cancer. A number of agents directed against these products have been produced. In vitro studies have shown the effectiveness of this strategy and phase I-II clinical trials have yielded promising results. However, a lot of work has yet to be done to overcome a variety of challenges. Any pharmacological intervention has to be specific in order to increase effectively the radiation therapeutic ratio. Such specificity for tumor or normal tissue can be obtained by exploiting molecular differences between normal and malignant cells, but cell kill depends on multifactorial mechanisms and exactly how the blockage of a specific pathway may affect radiation tumor response in human malignancies is yet to be addressed. Clinical research has to define how these new agents are integrated with radiotherapy and chemotherapy. Indeed, novel targeting approaches for tumor radiosensitization is an evolving area of active translational and clinical research in radiation oncology. This review provides an update on the status of some of these novel targets for human tumor radiosensitization.