Hypoxic cell radiosensitizers: expectations and progress in drug development

When misonidazole (MISO) was introduced into clinical trials there were great expectations that the cure rate of many tumors would be dramatically increased. The lack of efficacy of MISO discouraged further studies with hypoxic cell sensitizers. In recent years superior sensitizers SR 2508 and RO-03-8799 have been introduced into the clinic. SR 2508 is less neurotoxic than MISO, allowing more than three times the total amount of drug to be administered. Furthermore, based on the analysis of a patient's plasma pharmacokinetic profile, neurotoxicity may be largely avoidable. RO-03-8799 is superior in that it produces a higher sensitizer enhancement ratio than MISO for the same administered dose. Unlike with MISO and SR 2508, the dose of RO-03-8799 that can be administered is limited by acute toxicity with no cumulative toxicity having yet been encountered. The lack of overlapping toxicities of RO-03-8799 and SR 2508 may permit their simultaneous use with radiation thereby further increasing the utility of this class of compounds. Study design has improved and the expected clinical benefit from sensitizers has been clarified. Sensitizers, like particle radiation therapy and hyperthermia will, if successful, effect the rate of local tumor control, but cannot improve the cure rate of patients with preexisting metastatic disease. Taking into account the need to optimize reoxygenation, the various reasons for tumor radioresistance other than hypoxia, and the lower oxygen and sensitizer enhancement ratios at 200 cGy per fraction, it is likely that sensitizers will provide some clinical benefit for patients with selected tumor types. Future trials with sensitizers may not only provide clinical benefit but may help answer the question as to the role of hypoxia in clinical radiotherapy.