Radiation sensitization with redox modulators: a promising approach.

Radiation therapy plays a critical role in the local and regional control of malignant tumors. Its efficacy, however, is limited by a number of factors, including toxicity, tumor hypoxia, and tumor genetics. Recent attempts to enhance the efficacy of radiation therapy have focused on biologic agents that modulate reduction/oxidation reactions within tumor cells. We review five promising redox modulators that are in development. Tirapazamine and AQ4N are known as "hypoxic cell sensitizers" and are toxic in areas of low oxygen tension. RSR13 facilitates delivery of oxygen to tumor cells, thereby rendering them more sensitive to radiation. Motexafin gadolinium, with a porphyrin-like structure, selectively accumulates in tumor cells and thereby enhances radiation-induced DNA damage. HIF-1 inhibitors target a transcription factor that regulates hypoxia-related events and cell survival. Our review of each agent included a thorough search of published preclinical and clinical data, including that presented in abstracts and posters at international meetings. Our objectives were not to identify a superior mechanism or drug, but rather to summarize the available safety and efficacy data. Clearly, there is an unmet need for safer agents that augment the efficacy of radiation therapy. This review highlights five promising redox modulators that are in development. None has yet been approved by the Food and Drug Administration. These drugs were selected for discussion because they exemplify the current investigative landscape of radiosensitizers and are indicative of future directions in this area. These radiation sensitizers have the potential to succeed where others have failed, by locally increasing the radiosensitivity of tumor cells without enhancing that of surrounding normal tissues.