Chapter 16. Radiosensitizers

Publisher Summary Radiation therapy is an important treatment modality for many forms of human cancer. Although this therapeutic approach is effective in many cases, normal tissue toxicity limits the total dose of radiation a patient can receive. Many tumors contain areas of diminished oxygen concentration that make them more resistant to the lethal effects of radiation. Advances in instrumentation and technology have provided radiotherapists with the means of targeting X-rays more precisely and eliminating some of the normal tissue damage. Physiological differences that exist between the tumor cells and normal tissues have been exploited to develop a number of clinical candidates. However, most of these compounds have failed because of a lack of potency or as a result of direct toxicity of the drug at therapeutic doses. These studies, although clinically unsuccessful, have provided information that has been useful in the design and development of new approaches and agents. This chapter discusses the progress in enhancing the effectiveness of radiotherapy and describes the use of chemical agents that, through a variety of mechanisms, selectively sensitize tumors to the lethal effects of X-rays. The most widely studied approach is the use of oxygen mimetics, which are compounds with specific physical properties (reduction potential, pKa, and log P) and which are able to penetrate into tumors and cause DNA damage by a mechanism similar to that of oxygen. The modifiers of oxygen utilization that increase the oxygen concentration in tumors or inhibit its metabolic use and repair inhibitors that interfere with the processes involved in the repair of radiation-induced DNA damage are evaluated in the chapter. In the study described in the chapter, clinical reevaluation of the use of halogenated pyrimidines as radiosensitizers was undertaken. Previous clinical studies were hampered by normal tissue toxicity and difficulties with drug administration.